sirolimus and Pancreatic-Neoplasms

Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles.. This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC.. Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords.. Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; ErbB Receptors; Fluorouracil; Humans; Metformin; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Resveratrol; Sirolimus; TOR Serine-Threonine Kinases

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Pancreatic neuroendocrine tumors (pNETs) are a rare and heterogeneous group of neoplasia. Presentation of these tumors can vary widely. Current treatment modalities range from potentially curative surgical interventions in localized disease to the use of varied hormonal analogues, cytotoxic agents and targeted therapy for the management of locally advanced and metastatic disease. With such a wide variety of therapeutic modalities, clinicians are faced with the task of building an effective and comprehensive treatment strategy for their patients.. Targeted therapy for pNET is limited to sunitinib and everolimus. There have been a number of important studies assessing the efficacy of other targeted agents, in addition to the conjugation of these agents in the management of advanced pNET. This review will stand to highlight currently available targeted therapies for the treatment of advanced pNET.. The use of targeted agents in the management of advanced pNET has significant potential to change the current standard of care. In addition to the use of long-acting somatostatin analogues, targeting the mammalian target of rapamycin and vascular endothelial growth factor pathways can be well tolerated and may lead to long periods of disease control in a wide variety of neuroendocrine tumors involving the pancreas.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a heterogeneous group of diseases. Advanced GEP-NENs are considered distinct disease entity with limited treatments. In this review, we will explore the biological rationale and clinical data of everolimus-based combinations for advanced GEP-NENs. PubMed/Medline, the Cochrane Library, and Google Scholar were searched using the terms "GEP-NENs" and "everolimus" and "systemic therapy" and selecting English literature only. Outcomes of interest included progression-free survival and overall survival (PFS and OS), toxicities, and tumor response. A total of 14 potentially relevant trials were initially identified, of which five studies were excluded. Hence, nine trials including 699 patients were included. Median PFS was reported in four out of the nine studies ranging from 14.6 to 16.4 months. The disease control rate was reported in all studies, and it ranged from 75 to 93%. Frequently reported grade 3/4 toxicities were elevated transaminases, hyperglycemia, and hematologic toxicities. The presence of clinical and statistical heterogeneity of the primary studies precludes reliable evidence-based conclusions. Further well-conducted randomized controlled trials are awaited to better evaluate the treatment of GEP-NENs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Gastrointestinal Neoplasms; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; PubMed; Sirolimus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The systemic management of patients with pancreatic neuroendocrine tumors includes chemotherapy and targeted agents such as everolimus and sunitinib. Which treatment to favor in a particular patient is not known. The most commonly used chemotherapy agents are streptozocin and temozolamide, often prescribed in combination with fluoropyrimidines. A potential biomarker for selection of temozolomide-based chemotherapy is O-6-methylguanine-DNA-methyltrasferase expression. Chemotherapy yields higher response rates and may be preferable in patients with higher-grade tumors and those who are symptomatic. The mammalian target of rapamycin inhibitor everolimus has shown improvement in progression-free survival (PFS) in a robust, well-conducted phase III study. Everolimus, however, can induce limiting toxicities that may result in treatment discontinuation and does not improve survival. However, the objective response rate is very low. Sunitinib, likewise, increases PFS but the data comes from a smaller trial which was terminated early. Sunitinib displays a different toxicity profile and is associated with a trend towards improved overall survival. It is clear that biomarkers to properly select the most effective agents in an individual patient are needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease-Free Survival; DNA Modification Methylases; DNA Repair Enzymes; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome; Tumor Suppressor Proteins

Medical management of pancreatic neuroendocrine tumors has recently been improved by new molecules of which the mTOR inhibitor everolimus. If digestive neuroendocrine tumors are rare, the incidence is in constant increase and the prevalence in digestive cancers put them right behind colorectal cancers. Everolimus has demonstrated efficacy in unresectable and progressive pancreatic neuroendocrine tumors, by doubling the median progression free survival (11 versus 4.6 months), with a median time of exposure to everolimus of nine months. Everolimus is generally maintained until progression or intolerance and some patients are treated during several years. Potential metabolic disorders induced by everolimus (dyslipidemia, hyperglycemia) in patients with life expectancy of several years, justify monitoring of these parameters and accurate treatment management algorithm. These will avoid worsening patient's prognostic, but also prematurely discontinue potentially effective treatment or contraindicate other therapeutic weapons, in a pathology in which there are multiple therapeutic options in metastatic phase. We propose a standard practice in terms of initial assessment, monitoring, care threshold, and therapeutic objectives to manage metabolic disorders, fitted to our patients with advanced pancreatic neuroendocrine tumors.

Topics: Dyslipidemias; Everolimus; Humans; Hyperglycemia; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus

Neuroendocrine tumors (NET) of the pancreas are uncommon neoplasms that arise from the pancreatic islet cells. Surgical resections are being tested, as well as multiple chemotherapy agents. Current treatment options for nonresectable disease include somatostatin analogs and chemotherapy. New therapies focus on specific molecular targets such as sunitinib, angiogenesis inhibitor, that target vascular endothelial growth factor receptor (VEGFR) and other growth factor receptors and everolimus, an inhibitor of the mammalian target of rapamycin. Functionally based medical therapies for NET include somatostatin analogs to control symptoms. The 2014 annual meeting of American Society of Clinical Oncology (ASCO) brought us new insights into the management of pancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#e15160 and #e15161), that shed light on new therapeutic options that help target the unique pathways of this malignancies.

Topics: Antineoplastic Agents; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; Survival Analysis; Treatment Outcome

Topics: Antineoplastic Agents; Everolimus; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Peptides, Cyclic; Sirolimus; Somatostatin

Topics: Antineoplastic Agents, Hormonal; Everolimus; Gastrointestinal Neoplasms; Humans; Immunosuppressive Agents; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Sirolimus; Somatostatin; Surgical Procedures, Operative

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is implicated in the pathogenesis of pancreatic neuroendocrine tumors (pNETs). Activation of this pathway is driven by aberrant tyrosine kinase receptor activities. Mutations in the PI3K/Akt/mTOR pathway occur in 15% of pNETs, and expression of genes of the PI3K/Akt/mTOR pathway is altered in the majority of pNETs. The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent mTORC2-mediated activation of Akt. Specific inhibitors of PI3K, Akt, or other pathway nodes, and their concomitant use with mTOR inhibitors, or agents with dual activity, may be more effective. Preclinical studies demonstrate that inhibitors of the PI3K pathway have antitumor activity in pNET cells, either through direct inhibition of individual pathway nodes or indirect inhibition of molecular chaperones such as heat-shock protein 90. Clinical studies are underway evaluating individual node and dual node inhibitors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Everolimus; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The incidence of neuroendocrine tumors (NET) has increased dramatically in the past 30 years. This information has revitalized basic and clinical research into the molecular biology of NET and has resulted in the recent approval of new therapies for pancreatic NET (pNET), including the oral inhibitor of the mTOR everolimus. Everolimus significantly improved progression-free survival among patients with pNET in the phase III RADIANT-3 study. Here, we review the clinical studies showing the efficacy of everolimus in pNET and summarize the translational science from these studies. To understand the mechanisms of resistance and cause of treatment failure, we compared the type of progression events observed in the everolimus and placebo arms of the RADIANT-3 study. Comparison of the everolimus arm to the placebo arm indicated the fractions of progression events due to new metastasis only (21% vs. 22%), growth of preexisting lesions only (54% vs. 49%), and new metastasis along with growth of preexisting lesions (24% vs. 27%) were similar. These results suggest that although everolimus delays disease progression in patients with pNET, patients who experience disease progression while on everolimus do not appear to have a more aggressive metastatic phenotype than those whose disease progresses while on placebo.

Topics: Clinical Trials as Topic; Everolimus; Humans; Immunosuppressive Agents; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Neuroendocrine tumors (NET) are a diverse group of tumors that derive from epithelial cells with neuroendocrine differentiation. Gastroenteropancreatic neuroendocrine tumors are a subset of NET that arises in the gastrointestinal tract. Clinical symptoms and presentations vary depending on the location and hormones produced by the tumor. Treatment of advanced and metastatic gastroenteropancreatic NETs has traditionally been difficult with few systemic treatment options. In 2011, two new targeted therapies, everolimus and sunitinib were approved for treatment of pancreatic NET leading to increased interest in novel agents active in gastroenteropancreatic NETs. At the 2013 ASCO Gastrointestinal Cancers Symposium two abstracts presented new data regarding novel therapies. Lombard-Bohas et al. (Abstract #224) presented new data from the RADIANT-3 trial and Shen et al. (Abstract #322) looked at the use of octreotide in elderly patients with carcinoid syndrome.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Drugs, Investigational; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib

Neuroendocrine tumors (NET) are a diverse group of tumors that derive from epithelial cells with neuroendocrine differentiation. Gastroenteropancreatic NETs are a subset of NET that arise from the gastrointestinal tract. The natural history and prognosis varies widely between different gastroenteropancreatic NETs, highlighting the importance of identifying accurate prognostic and predictive biomarkers. At the 2013 ASCO Gastrointestinal Cancers Symposium, De Braud et al. (Abstract #186) and Bellister et al. (Abstract #163) present data on two new possible biomarkers.

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Biomarkers, Tumor; Everolimus; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphoprotein Phosphatases; Polymorphism, Single Nucleotide; Prognosis; Sirolimus

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene knock-out/knock-in studies indicate that inactivation of factors including MEN1 and abnormal PI3K/mTOR signaling uncouples endocrine cell cycle progression from the control of environmental cues such as glucose, leading to islet cell overgrowth. In addition, accumulating evidence suggests that further impairment of endothelial-endocrine cell interactions contributes to tumor invasion and metastasis. Recent phase III clinical trials have shown that therapeutic interventions, such as sunitinib and everolimus, targeting those signal transduction pathways improve disease-free survival rates. Yet, cure in the setting of advanced disease remains elusive. Further advances in our understanding of the molecular mechanisms of PanNETs and improved preclinical models will assist in developing personalized therapy utilizing novel drugs to provide prolonged control or even cure the disease.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Cell Hypoxia; Co-Repressor Proteins; Cyclin-Dependent Kinase Inhibitor p18; Disease Progression; Disease-Free Survival; Everolimus; Gene Knock-In Techniques; Gene Knockout Techniques; Genetic Predisposition to Disease; Humans; Indoles; Islets of Langerhans; Molecular Chaperones; Molecular Targeted Therapy; Mutation; Neovascularization, Pathologic; Neuroendocrine Tumors; Nuclear Proteins; Octreotide; Pancreatic Neoplasms; Proto-Oncogene Proteins; Pyrroles; Receptor, Notch1; Signal Transduction; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

A better understanding of molecular mechanisms responsible for tumorigenesis has allowed the development of targeted drugs designed to improve the outcome of cancer. In endocrine tumors, several molecules have demonstrated efficacy in terms of progression free survival during phase III trials such as vandetanib and cabozantinib in medullary thyroid carcinoma, sorafenib in differentiated thyroid carcinoma and everolimus or sunitinib for pancreatic neuroendocrine tumors. Rare cancer network has allowed ongoing phase III trials in malignant pheochromocytoma and adrenocortical carcinoma. However, to date no specific predictive biomarker has yet been identified for a personalized cancer medicine. We review recent advances in endocrine oncology concerning molecular targets identification, targeted therapies and predictive or prognostic markers.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Disease-Free Survival; Endocrine Gland Neoplasms; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Piperidines; Prognosis; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; Thyroid Neoplasms; Treatment Outcome

This review summarizes results of recent clinical trials regarding the treatment of advanced neuroendocrine tumours (NETs) and pancreatic NETs (PNETs).. Most NETs occur sporadically in the lung and the gastrointestinal tract, and their prevalence has apparently increased over the last decades. Although curative treatment can be accomplished by surgery, for some NETs, most present in advanced stages and alternative, medical therapy is indicated. Recent randomized clinical treatment trials using somatostatin analogues in well differentiated midgut NET and therapies targeting the mammalian target of rapamycin (mTOR) signalling pathway and various tyrosine kinases provided evidence of improved progression-free survival. Treatment of functional PNETs with the mTOR inhibitor everolimus also showed reduction of peptide secretion relevant to the presenting clinical syndrome.. Previous work regarding the molecular pathology of NETs identified mTOR and tyrosine kinase signalling pathways as relevant targets in the neuroendocrine tumour biology. Subsequently, recent randomized clinical trials targeting these pathways with inhibitor therapies have provided encouraging results demonstrating prolonged progression-free survival and improvement of secretion-related clinical syndromes.

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Disease-Free Survival; Everolimus; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Mice; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Neuroendocrine tumours are a heterogeneous group of neoplasms with various clinical presentations, growth rates and responses to available therapies. Studies published in 2012 have provided insights into tumour-cell signalling that will increase our knowledge of tumour biology and molecular genetics, making it possible to personalize patient care.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Everolimus; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Precision Medicine; Receptor, Fibroblast Growth Factor, Type 4; Signal Transduction; Sirolimus

Pancreatic neuroendocrine tumors (PNETs) are rare but are well understood to cover a broad spectrum of clinical presentation, tumor biology and prognosis. More than 60% of PNETs are diagnosed at advanced disease stage and are ineligible for surgical resection. Prior to 2011, streptozocin was the only approved agent for unresectable advanced PNETs. In recent years, breakthroughs in signal pathway research have led to the identification of new therapeutic targets and agents directed at the molecular level. In 2011, two new targeted therapeutic agents, sunitinib and everolimus, were approved by the Food and Drug Administration (FDA). Sunitinib is an inhibitor of multiple tyrosine kinases, and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. This review discusses the major signaling pathways that are frequently mutated or deregulated in PNETs, and the implications of molecular alterations for PNET therapy. Biologic therapy through targeting relevant pathways represents a promising approach in the therapy of advanced and unresectable PNETs.

Topics: Antineoplastic Agents; Everolimus; Humans; Immunosuppressive Agents; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein-Tyrosine Kinases; Pyrroles; Signal Transduction; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Somatostatin; Sunitinib; Treatment Outcome

Pancreatic neuroendocrine tumours (pNETs) are relatively rare and generally felt to follow an indolent course. But poorly differentiated tumours can behave aggressively with 5-year survival ranging from 31% to 48%. Recent data suggest that patients with pNETs may derive benefit from treatment targeting the molecular changes expressed in this tumour group. This article describes advances in the treatment of unresectable pNETs that have led to a doubling of progression free survival.

Topics: Antineoplastic Agents; Disease-Free Survival; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib

Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (panNETs). Recently, two therapies have been FDA approved for progressive well-differentiated pancreatic NETs but have not been submitted for use in carcinoid tumors (Yao, Shah, Ito, et al. N Engl J Med 364:514-23, 2011••; Raymond, Dahan, Raoul, et al. N Engl J Med 364:501-13, 2011••). The first is sunitinib (Sutent(®), Pfizer, Inc.), an orally administered, multitargeted receptor kinase inhibitor. The second targeted agent is everolimus (Afinitor(®), Novartis Pharmaceuticals), a mammalian target of rapamycin (mTOR) inhibitor (Yao, Shah, Ito, et al. N Engl J Med 364:514-23, 2011••). Both agents demonstrated improved progression-free survival but can also result in non-trivial toxicities and therefore, should only be considered in patients with progressing or symptomatic pancreatic NET. This review will discuss "new" NET therapies and provides an overview of liver directed and "older" cytotoxic treatment options. We also briefly outline "what's different" by describing a recent genetics report identifying genetic mutations in panNETs. Such a discovery could potentially be used to stratify treatment and such studies are currently being investigated.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoid Tumor; Combined Modality Therapy; Dacarbazine; Embolization, Therapeutic; Everolimus; Humans; Immunosuppressive Agents; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Streptozocin; Sunitinib; Temozolomide; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factors; Yttrium Radioisotopes

After years of limited progress in the treatment of patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs), strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumors. Some of these agents, targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have shown efficacy in randomized clinical trials. The tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have received international approval for the treatment of advanced well differentiated pancreatic NETs after showing survival benefit in randomized phase III trials. There is now an imperative need to identify biomarkers of the biologic activity of such targeted therapies in specific disease contexts, as well as new markers of response and prognosis. This approach may allow rational development of drugs and early identification of patients who may obtain benefit from treatments. In this article, we review recent developments in circulating biomarkers of the clinical benefit of targeted therapies for GEP-NET, including soluble proteins and circulating cells, with an emphasis on sunitinib. No validated molecular biomarkers are yet integrated into clinical practice for sunitinib in NET, although some markers have shown correlation with clinical outcomes and may be implicated in resistance. The VEGF-pathway proteins and interleukin-8 (IL-8) are possibly prognostic in GEP-NET; other possible soluble markers of the activity of sunitinib and everolimus include stromal cell-derived factor 1α, chromogranin A, and neuron-specific enolase. We additionally discuss treatment-induced modulation of circulating endothelial cells and progenitors and subpopulations of cells of the myeloid lineage. These candidate markers should be considered in the development of future combination or sequential therapies.

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Biomarkers, Tumor; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Interleukin-8; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Neuroendocrine carcinomas are rare neoplasms although of increasing incidence and concern. While traditionally considered of indolent nature, once they progress beyond surgical resectability, the outcome is ultimately fatal for the majority of patients. Somatostatin analogs are useful to control symptoms in functioning tumors and may slow tumor progression in certain disease settings, but sensitivity to conventional cytotoxic chemotherapy is rather limited. In this context, results of the recently published randomized trials with sunitinib and everolimus have demonstrated for the first time that there are agents able to positively impact on the natural history of this complex disease. In this review, we will discuss available data on angiogenesis and mammalian target of rapamycin inhibitors for the treatment of advanced well-differentiated gastroenteropancreatic neuroendocrine tumors.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Molecular Targeted Therapy; Neovascularization, Pathologic; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Although neuroendocrine tumors (NET) are a relatively rare malignancy, the reported incidence is increasing, and some of the current treatment options are limited in their efficacy. Standard first-line therapy for metastatic small bowel NET includes somatostatin analogs. Although these agents can provide symptom relief and can delay disease progression in many patients, ultimately, new treatments are required for patients with progressive disease. In recent years, there has been considerable interest in developing agents specifically targeted against some of the pathways known to be involved in cancer cell growth, survival and invasion. In 2011, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib were approved for the treatment of pancreatic NET. Clinical trials evaluating novel targeted agents are ongoing, both as single agents and in combination regimens. We review the current clinical status of these potential new treatments and highlight those with particular promise for the management of well-differentiated NET.

Topics: Antineoplastic Agents; Benzenesulfonates; Cell Differentiation; ErbB Receptors; Everolimus; Histone Deacetylases; Humans; Immunologic Factors; Indazoles; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Receptors, Somatostatin; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited.. A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA. This review discusses this landmark discovery in the context of currently available therapeutic options, pathophysiology and molecular genetics of PNET.. The approval of everolimus for the treatment of PNET marks a major step forward in the clinical management of this disease and represents a notable example of the successful translation of a targeted therapy that was initially developed based on findings at the lab bench, into everyday clinical practice. These results encourage hopes that the overall therapeutic efficacy of such approaches can be further enhanced by the introduction of combinatorial regimens, simultaneously targeting more than one oncogenic signaling pathway, as well as by stratification of patients based on the individual genetic setup of their tumors.

Topics: Antineoplastic Agents; Everolimus; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Resistance, Neoplasm; Etoposide; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Medical Oncology; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

To present the current clinical evidence on everolimus for use in pancreatic neuroendocrine tumors (pNET).. A literature search was performed using PubMed and MEDLINE (1946-March 2012). Search terms were everolimus, RAD001, mTOR inhibitor, and pancreatic neuroendocrine tumors. Abstracts from the American Society of Clinical Oncology 2000-2012 meetings and Food and Drug Administration (FDA) reviews were searched to obtain otherwise unpublished data. The national clinical trials registry was searched for current and future studies of everolimus in pNET.. Clinical studies available in the English language describing the pharmacology, pharmacokinetics, clinical activity, and safety of everolimus in pNET were included. All peer-reviewed, clinically relevant publications were reviewed for inclusion.. Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved by the FDA in May 2011 for the treatment of progressive, advanced pNET. Everolimus exerts its effect by inhibiting multiple downstream pathways of mTOR, which decreases cell proliferation, survival, and angiogenesis. Its pNET indication was based on the results of RADIANT-3, a Phase 3 trial demonstrating increased median progression-free survival (11 months) with everolimus 10 mg orally once daily compared to placebo (4.6 months). Everolimus was well tolerated in clinical trials. The most commonly reported adverse events included stomatitis, rash, diarrhea, fatigue, infections, nausea, and decreased appetite. Grade 3/4 events including anemia, thrombocytopenia, pneumonitis, and hyperglycemia occurred in approximately 5% of patients.. Based on review of the available literature, everolimus is a safe and effective treatment option for patients with low- to intermediate-grade, unresectable or metastatic pNET that have progressed on prior therapies. Until results of head-to-head, randomized controlled trials are conducted to compare everolimus to other treatment options, it cannot be said whether everolimus is more efficacious or tolerable than other treatment options.

Topics: Antineoplastic Agents; Everolimus; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Dacarbazine; Digestive System Surgical Procedures; Everolimus; Humans; Immunosuppressive Agents; Indoles; Japan; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Somatostatin; Streptozocin; Sunitinib; Temozolomide

In a placebo-controlled trial, the median time to radiologic documentation of cancer worsening or death was extended by about 6 months, although patients experienced many, often serious, adverse effects.

Topics: Antineoplastic Agents; Everolimus; Evidence-Based Medicine; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Patient Safety; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Pancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their rareness and due to their benign behavior a considerable prevalence. Pathogenesis of pancreatic neuroendocrine tumors is characterized by common pathways of hereditary and sporadic tumors. Pancreatic neuroendocrine tumors may secrete peptide hormones or biogenic amines in an autonomous fashion as functional active tumors. Pathological grading and staging by TNM systems has been established in recent years classifying well and moderately differentiated pancreatice neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Chromogranin A and less so pancreatic polypeptide are suitable tumor markers for pancreatic neuroendocrine tumors. Expression of receptors for somatostatin is the basis of treatment of pancreatic neuroendocrine tumors with somatostatin analogues as antisecretive and antiproliferative agents. In addition, somatostatin scintigraphy or PET/CT allows comprehensive diagnosis of pancreatic neuroendocrine tumors, which should be supported by (endoscopic and contrast enhanced) ultrasound, CT and MRI. Therapy of pancreatic neuroendocrine tumors consists of somatostatin analogues, chemotherapy, targeted therapy and peptide receptor radionuclide therapy. Two molecular substances hav been registered for pancreatic neuroendocrine tumors recently, sunitinib (Sutent®) and everolimus (Afinitor®). Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chromogranin A; Endosonography; Everolimus; Germany; Hepatectomy; Humans; Incidence; Indoles; Liver Transplantation; Magnetic Resonance Imaging; Multimodal Imaging; Neoplasm Grading; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Positron-Emission Tomography; Prevalence; Prognosis; Pyrroles; Sirolimus; Somatostatin; Sunitinib; Tomography, X-Ray Computed; Treatment Outcome

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

Topics: Antineoplastic Agents; Everolimus; Humans; Indoles; Insulinoma; Liver Neoplasms; Pancreatic Neoplasms; Pyrroles; Radiopharmaceuticals; Receptors, Somatostatin; Sirolimus; Somatostatin; Sunitinib

Approximately two-thirds of neuroendocrine tumours (NET) occur in the gastrointestinal tract and over 60% present with metastases. With greater insight into molecular pathways involved in tumour progression, opportunities are presented for the use of targeted therapies in NET. Although a wide array of targeted agents has been investigated, only a handful has emerged as forerunners from recent clinical trials. This literature review focuses on the use of anti-angiogenic monoclonal antibody bevacizumab, as well as small molecule inhibitors sunitinib and everolimus.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Endocrine Gland Neoplasms; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Molecular Targeted Therapy; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Survival from pancreatic neuroendocrine tumors has not improved over the past two decades and, until recently, streptozocin was the last therapeutic agent approved for this malignancy. Everolimus blocks mTOR, which plays an integral role in cell growth, mitosis and angiogenesis. Abnormal PI3K-Akt/PKB-mTOR pathway signaling has been implicated in the pathogenesis of pancreatic neuroendocrine tumors. In a Phase III study, patients with low- and intermediate-grade advanced pancreatic neuroendocrine tumors were randomized to receive everolimus 10 mg/day or placebo. Median progression-free survival was significantly greater in patients treated with everolimus than placebo - 11 versus 4.6 months - and drug-related adverse events were consistent with the known side-effect profile of everolimus. Everolimus represents a significant treatment development for pancreatic neuroendocrine tumors.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Drug Evaluation, Preclinical; Everolimus; Humans; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Sirolimus

Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebo-controlled phase III trials using 2 drugs--everolimus and sunitinib--with distinct molecular rationales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defining the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting.. Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies.

Topics: Clinical Trials as Topic; Drug Discovery; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib

Surgical excision has been the mainstay of treatment for neuroendocrine tumors of the pancreas (PNET). Compounds like streptozocin and dacarbazin have been traditionally used in inoperable cases and somatostatin to treat syndromes deriving from functional tumors. However, a lot of progress has taken place in the area of molecular characterization of these tumors, revealing activation of mammalian target of rapamycin (mTOR) and VEGF pathways. Recent data from the 2010 ASCO Gastrointestinal Cancers Symposium demonstrate antitumor activity of everolimus, an mTOR inhibitor in combination with temozolomide in a phase I/II trial and of sunitinib versus placebo in a randomized double blinded phase III trial. The role of modern biologic compounds in the treatment of PNET is not clear yet. In addition, combination of resection and transarterial chemoembolization (TACE) has been proven effective over either modality alone in the treatment of PNET metastatic to the liver in a retrospective analysis. This comes to address the problem of selecting local intervention in a metastatic disease, which has been a reasonable choice for this group of tumors in the past. Last but not least the role of Ki-67 in decision-making in PNET is being discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoembolization, Therapeutic; Clinical Trials as Topic; Combined Modality Therapy; Congresses as Topic; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Medical Oncology; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Retrospective Studies; Sirolimus; Sunitinib

Metastatic pancreatic cancer is often one of the most challenging malignancies a medical oncologist faces. Although the primary endpoint of many studies remains overall survival, palliation and quality of life are now more commonly being addressed. The author discusses the most common chemotherapeutic modalities for the treatment of metastatic pancreatic cancer, such as single agent chemotherapy, combination therapy, targeted therapy, and second line treatment.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Deoxycytidine; ErbB Receptors; Erlotinib Hydrochloride; Everolimus; Fluorouracil; Gemcitabine; Humans; Immunosuppressive Agents; Irinotecan; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Quality of Life; Quinazolines; Sirolimus

Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Neuroendocrine; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Pancreatic Neoplasms; Pyrroles; Receptors, Somatostatin; Sirolimus; Somatostatin; Sunitinib; Vascular Endothelial Growth Factor A

Traditional treatments for patients with advanced neuroendocrine tumors include surgical debulking, hepatic embolization, somatostatin analogues, and interferon-alpha. Patients with pancreatic neuroendocrine tumors also may benefit from treatment with the alkylating agents streptozocin or temozolomide. In recent years, several promising new approaches have been investigated in patients with advanced neuroendocrine tumors. One such approach has been the use of radiopeptide therapy targeting somatostatin receptors. Additionally, agents targeting the vascular endothelial growth factor pathway and mammalian target of rapamycin have shown preliminary evidence of activity and are currently being evaluated in large randomized studies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Combined Modality Therapy; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pyrroles; Radiopharmaceuticals; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Benzamides; Benzenesulfonates; Bevacizumab; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Deoxycytidine; Drug Delivery Systems; Gastrointestinal Stromal Tumors; Gemcitabine; Humans; Imatinib Mesylate; Indoles; Neoplasms; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Piperazines; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sunitinib

This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1).. Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01).. SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC.. gov Identifier: NCT03512756.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Humans; Methoxsalen; Pancreatic Neoplasms; Phenytoin; Quality of Life; Sirolimus

This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (PNETs) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3 mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n = 13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19 months (95% CI [3.84, 9.30]) and the median OS was 20.44 months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.

Topics: Humans; Mechanistic Target of Rapamycin Complex 1; MTOR Inhibitors; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs.. We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS.. A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%).. The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients.. Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate.. In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3).. The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Disease-Free Survival; Everolimus; Female; Fluorouracil; Humans; Male; Middle Aged; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long-acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin.. This was a phase 2, multicenter trial using a Simon's 2-stage minimax design. Treatment-naive patients with advanced well-differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR).. A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment-related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥ 6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, median time to progression and overall survival were not reached.. The everolimus-octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first-line treatment in patients with NET.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Female; Humans; Intestinal Neoplasms; Lung Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Sirolimus; Stomach Neoplasms

Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Everolimus; Female; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; Pancreas; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

Topics: Aged; Carcinoid Tumor; Compassionate Use Trials; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Sirolimus

Everolimus, an oral inhibitor of mammalian target of mTOR, has been recently shown to have antitumor effect in a phase III, double-blind, randomized trial (RADIANT-3) of 410 patients with advanced pancreatic neuroendocrine tumors (PNETs). The purpose of this study was to investigate the specific efficacy and safety of everolimus in the Chinese patient with PNETs. In this randomized phase II study, the analysis on Chinese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 44) and matching placebo (n = 35). The primary endpoint was progression-free survival (PFS). Adverse events were also examined. The median PFS was 15.47 months with everolimus [95% confidence interval (CI) 10.52-26.37], as compared to 4.29 months with placebo (95% CI 2.22-10.75), representing a 72% reduction in the risk of progression or death (hazard ratio 0.27; 95% CI 0.13-0.59; P < 0.001). Drug-associated adverse events (AEs) were mostly grade 1 or 2, observed in all 44 (100%) patients receiving everolimus and in 29 (83%) patients receiving placebo. The most common AEs (grade 1-4) associated with everolimus were rash (n = 38; 86%), stomatitis (n = 30; 68%), infections (n = 33; 75%), epistaxis (n = 32; 73%), pneumonitis (n = 27; 61%) and anemia (n = 22; 50%). Everolimus when compared with placebo is effectively in improving PFS in Chinese patients with PNETs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Double-Blind Method; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; Survival Rate

CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated.. Within a prospective single-centre study serial blood samples were collected from patients with confirmed advanced PC. Pre-treatment values and weekly measurements of CYFRA 21-1, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (assessed by Elecsys 2010, Roche Diagnostics) during palliative first-line chemotherapy were obtained. Biomarker data were correlated with objective response (determined by RECIST) as well as time to progression (TTP) and overall survival (OS) using uni- and multivariate analyses.. Seventy-eight patients were included, 45% of these received treatment in prospective clinical trials. Median TTP was 3.9 months, median OS 7.7 months. Pre-treatment CYFRA 21-1 levels were significantly associated with performance status (P=0.0399) and stage of disease (P=0.0001). Marker values before chemotherapy and at the 2-month staging of all three markers were considered significant predictors for objective treatment response. Pre-treatment CYFRA 21-1 levels, as well as CA 19-9 values, could be applied to define subgroups (categorised by tertiles) with a different OS outcome (CYFRA: 14.8 vs 7.1 vs 4.8 months, CA 19-9: 14.2 vs 7.1 vs 5.2 months; P<0.0001). CYFRA 21-1 and CA 19-9 (both as categorised and as continuous variables) showed a highly significant correlation with TTP and OS at nearly all-time points assessed in univariate analysis. In multivariate analysis, only CYFRA 21-1 and performance status were independent predictors for OS.. CYFRA 21-1 may serve as a valuable tool for monitoring treatment response and assessing prognosis in advanced PC.

Topics: Adult; Aged; Albumins; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Biomarkers, Tumor; CA-19-9 Antigen; Capecitabine; Carcinoembryonic Antigen; Deoxycytidine; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Fluorouracil; Gemcitabine; Humans; Imidazoles; Indazoles; Keratin-19; Middle Aged; Multivariate Analysis; Oximes; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Piperazines; Prospective Studies; Quinazolines; Sirolimus; Sulfonamides; Survival Rate

Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). A phase 1/2 study was performed to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients who have advanced pancreatic NET.. Patients were treated with temozolomide at a dose of 150 mg/m(2) per day on days 1 through 7 and days 15 through 21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival.. A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached.. Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Drug Administration Schedule; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Prospective Studies; Sirolimus; Temozolomide; Treatment Outcome

Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine.. Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5-10 mg/day) and capecitabine (600-800 mg/m(2) bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response.. Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m(2) bid for 2 weeks every 3 weeks and cetuximab 250 mg/m(2) weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1-6.8).. The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cetuximab; Deoxycytidine; Everolimus; Feasibility Studies; Female; Fluorouracil; Humans; Male; Middle Aged; Pancreatic Neoplasms; Sirolimus; Treatment Outcome

Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.. We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.. The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).. Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Double-Blind Method; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Proportional Hazards Models; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors.. The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus.. Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels.. In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study.. Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Prognosis; Sirolimus; Treatment Outcome

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromogranin A; Disease-Free Survival; Everolimus; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Sirolimus; Treatment Failure

The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models.. Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN.. Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers.. Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer.. NCT 0075647.. NCT00640978.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; ErbB Receptors; Erlotinib Hydrochloride; Everolimus; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Phosphorylation; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.. Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival.. Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as > or = 50% reduction in serum CA19-9.. Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.

Topics: Administration, Oral; Adult; Aged; Deoxycytidine; Drug Resistance, Neoplasm; Everolimus; Female; Gemcitabine; Humans; Male; Middle Aged; Oncogene Protein v-akt; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.. Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.. Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in >or= 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).. RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Carcinoma, Islet Cell; Delayed-Action Preparations; Everolimus; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Sirolimus

To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.. Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats.. Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses.. A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.

Topics: Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Humans; Immunosuppressive Agents; Models, Biological; Neoplasms; Pancreatic Neoplasms; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Neuroendocrine; Disease Progression; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Hyperglycemia; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome

Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase.

Topics: Adenocarcinoma; Animals; Beclin-1; Cell Line, Tumor; Cell Proliferation; Male; Mice; Pancreatic Neoplasms; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin inhibition has been shown to prolong progression-free survival in patients with pancreatic neuroendocrine tumors. The natural compound baicalein indirectly inhibits the mammalian target of rapamycin, but it is unknown if baicalein exhibits such effects at physiologically achievable concentrations or exhibits synergy.. Pancreatic neuroendocrine tumor cell lines were cultured with baicalein, everolimus, and/or a synthetic 5' adenosine monophosphate-activated protein kinase activating agent alone and in combination. Cell viability assays and immunoblotting were performed. Female severe combined immunodeficient-beige mice were injected with BON-1 cells and treated with baicalein and COH-SR4 solutions via oral gavage. Tumor volumes were compared at 30 days.. Immunoblotting revealed that treatment of baicalein induced 5' adenosine monophosphate-activated protein kinase activation and the mammalian target of rapamycin inhibition. Treatment with baicalein alone led to a significant decrease in the ratio of viable cells compared with controls at 72 hours at concentrations ≥5 μM (P = .021). The addition of COH-SR4 led to significantly greater effect on cell viability than with baicalein alone (P < .001, P < .001). The combination of baicalein with everolimus resulted in significantly lower cell viability than with everolimus alone (P = .005, P < .001). Tumor volume in vivo was significantly decreased with the combination of baicalein and COH-SR4 compared with controls (P = .003).. Baicalein exhibits antiproliferative effects against pancreatic neuroendocrine tumor cell lines at doses ≥5 μM and demonstrates synergy.

Topics: Adenosine Monophosphate; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Everolimus; Female; Mammals; Mice; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Resistance to immunotherapy and chemotherapy hinders the prognosis of pancreatic cancer(PC). We hypothesized that the combination of mTOR inhibitor sirolimus and gemcitabine would change the metabolic landscape of PC and enhance the anti-PD-L1 therapy.. In KPC mice, the following regimens were administered and tumor growth inhibition rates(TGI%) were calculated: sirolimus(S), PD-L1 antibody(P), gemcitabine(G), sirolimus + PD-L1 antibody(SP), sirolimus + gemcitabine(SG), PD-L1 + gemcitabine(PG) and sirolimus + PD-L1 antibody + gemcitabine(SPG). The metabolic changes of tumors were identified by LC-MS and subpopulations of immune cells were measured by flow cytometry. Sirolimus treated macrophages were co-cultured with PC cells in vitro, and the metabolic changes of macrophages and tumor cells as well as tumor cells' viability were detected.. The monotherapy of S, P and G didn't inhibit tumor growth significantly. The combination of SP, PG and SG didn't improve the TGI% significantly compared with monotherapy. However, the TGI% of SPG combination was higher than other groups. The proportion of CD68. mTOR inhibitor can change the immune microenvironment of PC via metabolic reprogramming, thus promoting the efficacy of PD-L1 blockade when combined with gemcitabine.

Topics: Animals; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Disease Models, Animal; Gemcitabine; Mice; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Tumor Microenvironment

Cuproplasia, or copper-dependent cell proliferation, has been observed in varieties of solid tumors along with aberrant copper homeostasis. Several studies reported good response of patients to copper chelator assisted neoadjuvant chemotherapy, however, the internal target molecules are still undetermined. Unravel copper-associated tumor signaling would be valuable to forge new links to translate biology of copper into clinical cancer therapies. We evaluated the significance of high-affinity copper transporter-1 (CTR1) by bioinformatic analysis, and in 19 pairs of clinical specimens. Then, with the help of gene interference and chelating agent, enriched signaling pathways were identified by KEGG analysis and immunoblotting. Accompanying biological capability of pancreatic carcinoma-associated proliferation, cell cycle, apoptosis, and angiogenesis were investigated. Furthermore, a combination of mTOR inhibitor and CTR1 suppressor has been assessed in xenografted tumor mouse models. Hyperactive CTR1 was investigated in pancreatic cancer tissues and proven to as the key point of cancer copper homeostasis. Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cell. PI3K/AKT/mTOR signaling pathway was suppressed by inhibiting the activation of p70(S6)K and p-AKT, and finally inhibited mTORC1 and mTORC2 after copper deprivation. Additionally, CTR1 gene silencing successfully improved the anti-cancer effect of mTOR inhibitor rapamycin. Our study reveals that CTR1 contributes to pancreatic tumorigenesis and progression, by up-regulating the phosphorylation of AKT/mTOR signaling molecules. Recovering copper balance by copper deprivation addresses as promising strategy for improved cancer chemotherapy.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Copper; Mechanistic Target of Rapamycin Complex 1; Mice; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death and has a poor 5-year overall survival. The superior therapeutic benefits of combination or co-administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA-loaded thermosensitive PLGA-PEG-PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA-PEG-PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc-1-luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75-fold higher inhibition rate than the non-treated (NT) and vehicle-treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti-tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti-cancer formulations.

Topics: Animals; Cell Line, Tumor; Gemcitabine; Hydrogels; Mammals; Mice; Pancreatic Neoplasms; Polyethylene Glycols; Polyglactin 910; Sirolimus

Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of ɑ-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Cisplatin; Lipopolysaccharides; Liposomes; Liver Neoplasms; Mice; Pancreatic Neoplasms; Peptides; Sirolimus

Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss.

Topics: Animals; Cadherins; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; GTP-Binding Protein alpha Subunits, G12-G13; Mice; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Sirolimus; TOR Serine-Threonine Kinases

Topics: Humans; Pancreatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic cancer has been characterized by poor prognosis, early metastasis and dissatisfactory treatment outcome. The high basal level of autophagy in tumor cells leads to chemoresistance and tumor progression. Thus, it is imminent to explore novel effective chemotherapeutic adjuvants to increase patients' survival rate. Isoliquiritigenin (ISL) is a bioactive flavonoid obtained from the Traditional Chinese herbal medicine Glycyrrhiza glabra, and it possesses a broad range of pharmacological effects. In this study, the anti-cancer effect of ISL in pancreatic cancer treatment and the underlying mechanism are investigated.. MTT assay, colony formation and EdU analysis were performed to explore the growth inhibition of ISL on pancreatic cancer cells. Apoptosis were analyzed using TUNEL and flow cytometry. The formations of autophagosomes were analyzed by immunofluorescence microscopy and transmission electron microscopy. RFP-GFP-LC3B probe was applied to detect the autophagy flux. To assess the structural interaction of ISL with p38 protein, molecular docking assays were performed. The molecular mechanism was elucidated by using western immunoblotting. Subsequently, the inhibition of ISL on tumor growth was determined in vivo using pancreatic tumor mice model.. ISL inhibited pancreatic cancer cell growth and induced apoptosis, both in vitro and in vivo. ISL caused accumulation of autophagosome through blockade of late stage autophagic flux. Moreover, autophagy inducer rapamycin enhanced ISL-evoked cell growth inhibition and promoted apoptosis, while inhibition of autophagosome formation by siAtg5 attenuated ISL-induced apoptosis. It is remarkable that ISL synergistically sensitized the cytotoxic effect of gemcitabine and 5-fluorouracil on pancreatic cancer cells as both drugs induced autophagy. Molecular docking analysis has indicated that ISL acted by direct targeting of p38 MAPK, which was confirmed by ISL-induced phosphorylation of p38. The autophagy flux induced by p38 inhibitor SB203580 was blocked by ISL, with further increasing toxicity of ISL in pancreatic cancer cells.. The results have revealed that ISL inhibited pancreatic cancer progression by blockade of autophagy through p38 MAPK signaling.

Topics: Animals; Apoptosis; Autophagy; Cell Line, Tumor; Chalcones; Drugs, Chinese Herbal; Fluorouracil; Mice; Molecular Docking Simulation; p38 Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Sirolimus

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

Topics: Animals; Antibiotics, Antineoplastic; Autophagy; Autophagy-Related Protein 5; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Feedback, Physiological; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Photosensitizing Agents; Sirolimus; Verteporfin; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

Topics: Everolimus; Humans; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Sirolimus

Topics: Everolimus; Humans; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Sirolimus

Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.. Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.. Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.. The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.

Topics: Adult; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Pancreatic Ductal; Drug Therapy, Combination; Female; Hedgehog Proteins; Humans; Immunosuppressive Agents; Male; Maximum Tolerated Dose; Middle Aged; Negative Results; Neoplasm Metastasis; Pancreatic Neoplasms; Pyridines; RNA, Neoplasm; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Animals; Antibiotics, Antineoplastic; Carcinogenesis; Disease Models, Animal; Gene Deletion; Mice; Neuroendocrine Tumors; Pancreatic Neoplasms; Proto-Oncogene Proteins; PTEN Phosphohydrolase; Sirolimus

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Perivascular epithelioid cell tumor, an extremely rare mesenchymal tumor, could be ubiquitous but rarely arises from pancreas. Surgery is considered the most appropriate treatment. Nevertheless, activation of mTOR pathway seems to be a common pathogenic event in PEComas paving the way to chemotherapy by mTOR inhibitor.. A 17 year-old man presented a hypervascular tumor of 55 mm, located in the head of pancreas without bile duct or pancreatic duct compression.. Histopathology showed epithelioid cells with clear or focally granular eosinophilic cytoplasm with melanocytic (HMB-45, Melan-A) and myoid markers which confirmed diagnosis of PEComa. Given the absence of worrisome feature, we ruled out surgery and decided to initiate treatment with Sirolimus, an mTOR inhibitor. After 3.5 years, we showed a significant reduction in size of the tumor.. This first case of pancreatic PEComa treated by mTOR inhibitor without surgery suggests a good efficiency of this therapy.

Topics: Adolescent; Humans; Magnetic Resonance Imaging; Male; Pancreas; Pancreatic Neoplasms; Perivascular Epithelioid Cell Neoplasms; Signal Transduction; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers.

Topics: Animals; Carcinoma, Pancreatic Ductal; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Metformin; Pancreatic Neoplasms; Signal Transduction; Sirolimus

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells

Topics: Animals; Carcinoid Heart Disease; Cell Line, Tumor; Drug Resistance, Neoplasm; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Mice; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrazines; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

To investigate whether Sirolimus could affect the glycolytic catabolism pathways of pancreatic carcinoma through the control of hypoxia induced factor (HIF-1α) to inhibit the growth of tumor, and explore the potential mechanism of targeting the signaling pathways of mTOR for the treatment of pancreatic carcinoma.. Sirolimus was applied to treat the pancreatic carcinoma in nude mice orthotopic transplantation model, its difference with the control group was compared; RT-PCR and Western blot were used to measure the mRNA and protein expression of mTOR, HIF-1α, Glucose carrier protein 1 (GLUT-1) and Hexokinase Ⅱ (HK-Ⅱ), respectively; the changes of activity of HK-Ⅱ in the tumor was determined.. The tumor mass of the control group (1.97±0.21)g was significantly larger than that of the Sirolimus group (0.38±0.10)g (P<0.01), and the volume of the control group (1.40±0.15) mm(3) was significantly larger than that of the Sirolimus group (0.27±0.07) mm(3) (P<0.01). The expressions of mTOR, GLUT-1 and HK-Ⅱ mRNA in the control group were higher than those of the Sirolimus group (P<0.05), while no significant change was observed in the expression of HIF-1α (P>0.05); the expressions of p-mTOR, HIF-1α, GLUT-1 and HK-Ⅱ proteins in the control group were higher than those of the Sirolimus group (P<0.05). The activity of HK-Ⅱ in the control group was higher than that of the Sirolimus group (P<0.05).. Sirolimus could affect the expression of GLUT-1 and HK-Ⅱ in pancreatic carcinoma through the effects of HIF-1α to inhibit tumor growth, indicating that blocking the mTOR pathway could control the glycolytic metabolism pathways of pancreatic carcinoma, which may become the new strategy for the treatment of pancreatic carcinoma.

Topics: Animals; Antibiotics, Antineoplastic; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 1; Hexokinase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Pancreatic Neoplasms; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.

Topics: Angiogenesis Inhibitors; Animals; Axitinib; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glucose; Glutamine; Glycolysis; Humans; Imidazoles; Indazoles; Indoles; Intestinal Neoplasms; Lactic Acid; Membrane Transport Proteins; Mice; Models, Biological; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Signal Transduction; Sirolimus; Stomach Neoplasms; Sunitinib; TOR Serine-Threonine Kinases; Up-Regulation

Neuroendocrine tumors (NETs) are a rare diverse group of malignancies occurring most commonly in the gastroenteropancreatic system and the lungs. The incidence of NETs is increasing worldwide; median survival for patients with metastatic NETs is 5-65 months. A growing body of evidence shows survival benefit in patients with advanced NETs (gastroenteropancreatic and lung) treated with mTOR inhibitor everolimus, with improvement in survival being demonstrated in the clinical trial and real-world setting. Everolimus has been shown to have a manageable safety profile, with the most common adverse events being stomatitis, rash, diarrhea, fatigue and infections. Due to the rarity of the condition, there are challenges in conducting clinical trials in these patients. Further research is required to clarify the role of adjuvant therapy, treatment sequencing and the use of multimodality treatments.

Topics: Clinical Trials as Topic; Combined Modality Therapy; Everolimus; Humans; Intestinal Neoplasms; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Respiratory System; Sirolimus; Stomach Neoplasms

Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.

Topics: Adult; Aged; Biomarkers, Tumor; Cell Survival; Everolimus; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Primary Cell Culture; Prognosis; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Cells, Cultured; Young Adult

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against glucolipotoxicity via activation of the Akt pathway. The present study investigated the protective effects of the GLP-1 analog liraglutide against cholesterol-induced lipotoxicity and the mechanisms involved.. The mouse βTC-6 pancreatic β-cell line was preincubated for 30 min with 10 nmol/L liraglutide alone or in combination with the mammalian target of rapamycin (mTOR) inhibitor rapamycin (1 μmol/L) before being exposed to 5 mmol/L cholesterol for 6 h. 4',6'-Diamidino-2-phenylindole (DAPI) staining and Western blot analyses were used to assess the effects of liraglutide on cholesterol-induced apoptosis and the phosphorylation of Akt and mTOR.. Cholesterol significantly promoted cell apoptosis and attenuated the phosphorylation of Akt and mTOR, effects that were significantly reversed by liraglutide. Furthermore, rapamycin pretreatment alone significantly increased cholesterol-induced apoptosis compared with cholesterol-treated cells without any other pretreatment.. The data indicate that mTOR signaling is an essential mediator in the protection of pancreatic β-cells against cholesterol-induced apoptosis by a GLP-1 analog.

Topics: Animals; Apoptosis; Blotting, Western; Cholesterol; Electrophoresis, Polyacrylamide Gel; Glucagon-Like Peptide 1; Hypoglycemic Agents; Immunosuppressive Agents; Insulinoma; Liraglutide; Mice; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle-regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.

Topics: Animals; Body Weight; Cell Cycle; Diet, Diabetic; Energy Intake; Glucose Intolerance; Hypoglycemic Agents; Immunosuppressive Agents; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Neoplasms, Experimental; Pancreatic Neoplasms; Prediabetic State; Random Allocation; Sirolimus; Snail Family Transcription Factors; Transcription Factors; Vimentin

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Erlotinib Hydrochloride; Everolimus; Humans; Indoles; Pancreatic Neoplasms; Pyrroles; Quinazolines; Sirolimus; Sunitinib

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Diarrhea; Drug Administration Schedule; Everolimus; Humans; Indoles; Ki-67 Antigen; Liver Neoplasms; Male; Middle Aged; Mitotic Index; Neoplasm Grading; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Somatostatin; Sunitinib; Tomography, X-Ray Computed

Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.. We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.. We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.. We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration-approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Everolimus; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neuroendocrine Tumors; Organic Chemicals; Pancreatic Neoplasms; Peritoneal Neoplasms; Protein Kinase Inhibitors; Pyrazines; Signal Transduction; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays

To study the effect of rapamycin on pancreatic cancer cell proliferation, we designed a serial of experiments in human pancreatic cancer cell line SW1990.. SW1990 cells were treated with different concentrations of rapamycin. Cell proliferation was measured by CCK-8 assay and cell colony formation. Cell cycle and apoptosis was analyzed by flow cytometry. The existence of mTOR signaling pathway was demonstrated by immunocytochemistry. Western-blot and real time-PCR were used to test whether mTOR-signaling pathway was inhibited with rapamycin treatment.. Our results showed that rapamycin inhibited the cell colony formation and proliferation (p < 0.05). Rapamycin induced G1 cell cycle arrest (p < 0.05) but not cell apoptosis (p > 0.05). p-mTOR, p-p70S6K and p-4E-BP1 were expressed in the cytoplasm of SW1990 cells and those proteins were significantly reduced with rapamycin (p < 0.05).. Rapamycin inhibits SW1990 pancreatic cancer cell proliferation through inhibiting the activation of mTOR pathway.

Topics: Antibiotics, Antineoplastic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Pancreatic Neoplasms; Signal Transduction; Sirolimus

Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options. Everolimus (RAD001), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTOR complex 1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone.. The BON cell line has been used as a model to study pancreatic neuroendocrine tumor cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), mitogen-activated protein kinase inhibitor PD0325901 (50 nM), PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002 (25 μM), or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage) and with LY29400 (subcutaneous) 1 week after intrasplenic injection of BON cells.. Cellular proliferation was most attenuated with the combination therapy of LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg per week, subcutaneous) and RAD001 (2.5 mg/kg per day) compared with that in the vehicle group (P = 0.04).. The combination therapy of LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared with vehicle or with single-drug therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Chromones; Disease Progression; Enzyme Inhibitors; Everolimus; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Mice; Mice, Nude; Morpholines; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Hypoglycemia poses a significant management challenge in patients with unresectable metastatic insulinoma. A 57-year-old woman with pancreatic neuroendocrine tumor with multiple liver metastases was referred to our institution. During the clinical course of pancreatic neuroendocrine tumor, she had experienced palpitations, cold sweats and faintness between meals that indicated her tumors had attained the characteristics of an insulinoma, and her quality of life was impacted by frequent hypoglycemic episodes which could not be prevented by conventional therapies. Shortly after the approval of everolimus for pancreatic neuroendocrine tumor in Japan, we began oral administration at 10 mg per day, which produced a rapid and substantial improvement in glycemic control. The serum insulin level decreased dramatically despite the tumor size remaining stable on computed tomography evaluation. Despite a dose reduction of everolimus to 5 mg per day in response to the adverse reaction of interstitial pneumonitis and a subsequent moderate increase in the serum insulin level, the patient has maintained normoglycemia for a year. Everolimus might represent the treatment of choice for unresectable insulinoma in terms of not only tumor stabilization but also glycemic control.

Topics: Administration, Oral; Antineoplastic Agents; Blood Glucose; Drug Administration Schedule; Everolimus; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Japan; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Quality of Life; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

To investigate the molecular mechanism of pancreatic cancer cell resistance to mammalian target of rapamycin (mTOR) inhibitor RAD001, and explore a feasible therapeutic strategy to overcome the resistance in patients with pancreatic cancer.. Western blotting was conducted to find out whether RAD001 induced c-Raf-ERK feedback activation and to identify whether RAD001 in combination with c-Raf inhibitor sorafenib could effectively block the feedback activation of c-Raf and downstream proteins. Sulphorhodamine B (SRB) colorimetric assay and colony formation were used to detect the effect of the combination treatment on cell growth and proliferation; finally, the effect on mouse subcutaneous xenografts was examined to confirm the efficacy of the combination treatment in vivo.. RAD001 effectively inhibited the expressions of mTORC1 and its downstream proteins, and induced the feedback activation of c-Raf. Whereas, RAD001 combined with c-Raf inhibitor sorafenib eliminated RAD001-induced activation of c-Raf-ERK pathway and reversed pancreatic cancer cell resistance to RAD001; compared with the RAD001 alone, sorafenib had a synergistical inhibitory effect with RAD001. And the tumor growth inhibitory effect of the combination was also proved in mouse subcutaneous xenografts in vivo.. RAD001-induced c-Raf-ERK feedback activation contributes to pancreatic cancer cell resistance to RAD001. Targeting of c-Raf may improve the therapeutic efficacy of RAD001 in patients with pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Metastasis; Pancreatic Neoplasms; Proto-Oncogene Proteins c-raf; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, unusually resistant against therapy. It is generally felt that stratification of patients for personalized medicine is the way forward. Here, we report that a subpopulation of PDACs shows strong activation of the mTOR signaling cassette. Moreover, we show that inhibition of mTOR in pancreatic cancer cell lines showing high levels of mTOR signaling is associated with cancer cell death. Finally, we show using fine needle biopsies the existence of a subpopulation of PDAC patients with high activation of the mTOR signaling cassette and provide evidence that inhibition of mTOR might be clinically useful for this group. Thus, our results define an unrecognized subpopulation of PDACs, characterized by high activation of mTOR and show that identification of this specific patient group in the early phase of diagnosis is feasible.

Topics: Antibiotics, Antineoplastic; Autophagy; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Flow Cytometry; Humans; Immunohistochemistry; Molecular Targeted Therapy; Pancreatic Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The Akt signaling pathway mediates a potent anti-apoptotic signal in pancreatic cancer and inhibition of this pathway has become an attractive mechanism to increase the efficacy of traditional chemotherapies. Autophagy is a lysosomal catabolic pathway by which eukaryotic cells recycle macromolecules and organelles. Although autophagy may function as a survival mechanism under metabolic stress conditions, it also serves as an alternate route to programmed cell death distinct from apoptosis. In the present study, we examined the role of autophagy in Akt-mediated regulation of cell death in pancreatic cancer.. Mia-PaCa-2 and PANC-1 human pancreatic cancer cell lines were used in our experiments. The small-molecule inhibitor A-443654 was used to inhibit Akt, and rapamycin was used to inhibit mTOR. Autophagy was inhibited with Chloroquine and 3-methyladenine. Autophagy was assessed by immunoblotting for light chain-3 (LC-3) processing as well as fluorescence microscopy for autophagosome formation following transfection with a LC-3/GFP construct. Cell death was determined by fluorescence-activated cell sorting (FACS) with quantitation of the sub-G0 content.. Inhibition of either Akt or mTOR induced autophagy; inhibition of Akt but not of mTOR led to traditional caspase-mediated apoptosis. When autophagy was inhibited, cell death was abrogated following Akt, but not mTOR, inhibition.. The Akt signaling pathway regulates both autophagy and apoptosis through divergent pathways; mTOR mediates autophagy signaling but appears to be un-involved in cell death. Autophagy appears to play a role in the regulation of cell survival by Akt, but only when proximal signaling pathways not involving mTOR are simultaneously activated.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Autophagy; Caspases; Cell Line, Tumor; Enzyme Activation; Humans; Indazoles; Indoles; Microscopy, Fluorescence; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.. Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.. We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.. KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Humans; Injections, Intraperitoneal; Mice; Mice, Mutant Strains; Mutation; Pancreatic Neoplasms; Positron-Emission Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Humans; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Everolimus; Humans; Imidazoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphorylation; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Everolimus, an mTOR inhibitor with immunosuppressive properties, is used in several types of advanced tumors. Materials and. We describe the first two cases of Pneumocystis jirovecii pneumonia in patients given everolimus for metastatic pancreatic neuroendocrine tumors.. The first patient presented with respiratory symptoms in the context of grade 4 lymphopenia 2 weeks after starting everolimus; the diagnosis of Pneumocystis jirovecii pneumonia was made post-mortem. After suspecting everolimus-related interstitial pneumonitis in the second patient, Pneumocystis jirovecii was detected, and cotrimoxazole therapy led to a favorable outcome.. Everolimus may induce pneumonitis, lymphopenia and opportunistic infections. The time from treatment initiation to opportunistic infection may be short. Risk factors in oncology deserve further identification in order to start prophylaxis without delay.

Topics: Antineoplastic Agents; Everolimus; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuroendocrine Tumors; Opportunistic Infections; Pancreatic Neoplasms; Pneumocystis carinii; Pneumonia; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

Topics: Adult; Amenorrhea; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Chemoembolization, Therapeutic; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Everolimus; Female; Humans; Immunohistochemistry; Liver Neoplasms; Menstruation; Pancreatic Neoplasms; Sirolimus; Tomography, X-Ray Computed

The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1 (loxp/loxp) mice, we generated the Neurog3-Tsc1-/- transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1-/- mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.

Topics: Animals; Antibiotics, Antineoplastic; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Carcinoma, Acinar Cell; Female; Humans; Immunohistochemistry; Liver Neoplasms; Lung Neoplasms; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Pancreas; Pancreatic Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Ultrasonography

Based on the significant prolongation of progression-free survival in a randomized phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial), everolimus has been approved for the management of advanced, progressive pancreatic neuroendocrine tumors (pNET). Here, we describe 15 participants in RADIANT-3 who were treated with everolimus at our study center. We report the long-term survival of a subset of patients.. Patients with advanced, progressive pNET were randomly assigned to the everolimus arm of RADIANT-3 or received everolimus as open-label treatment after experiencing progression on placebo or during the unblinded phase.. Five patients on everolimus (5-10 mg/day) had stable disease for >43 to >76 months after initiating treatment. Three patients achieved stable disease for 19-25 months, but died of progressive malignancy thereafter. Seven patients had stable disease for ≤11 months after initiating everolimus therapy.. Patients with advanced, progressive pNET can obtain long-term benefit from daily oral treatment with everolimus.

Topics: Adult; Aged; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus

The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis.

Topics: Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Hypoglycemic Agents; Indoles; Insulin; Metformin; Morpholines; Neurotensin; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Purines; Pyrimidines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

mTOR has been implicated in survival signals for many human cancers. Rapamycin and TGF-β synergistically induce G1 cell-cycle arrest in several cell lines with intact TGF-β signaling pathway, which protects cells from the apoptotic effects of rapamycin during S-phase of the cell cycle. Thus, rapamycin is cytostatic in the presence of serum/TGF-β and cytotoxic in the absence of serum. However, if TGF-β signaling is defective, rapamycin induced apoptosis in both the presence and absence of serum/TGF-β in colon and breast cancer cell lines. Because genetic dysregulation of TGF-β signaling is commonly observed in pancreatic cancers-with defects in the Smad4 gene being most prevalent, we hypothesized that pancreatic cancers would display a synthetic lethality to rapamycin in the presence of serum/TGF-β. We report here that Smad4-deficient pancreatic cancer cells are killed by rapamycin in the absence of serum; however, in the presence of serum, we did not observe the predicted synthetic lethality with rapamycin. Rapamycin also induced elevated phosphorylation of the survival kinase Akt at Ser473. Suppression of rapamycin-induced Akt phosphorylation restored rapamycin sensitivity in Smad4-null, but not Smad4 wild-type pancreatic cancer cells. This study shows that the synthetic lethality to rapamycin in pancreatic cancers with defective TGF-β signaling is masked by rapamycin-induced increases in Akt phosphorylation. The implication is that a combination of approaches that suppress both Akt phosphorylation and mTOR could be effective in targeting pancreatic cancers with defective TGF-β signaling.

Topics: Apoptosis; Cell Line, Tumor; Eukaryotic Initiation Factor-4E; Gene Knockdown Techniques; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Pancreatic Neoplasms; Phosphorylation; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Smad4 Protein; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions.. Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach.. PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib.. The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chromatography, Liquid; Drug Interactions; Everolimus; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Models, Biological; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Sirolimus; Sorafenib; Tandem Mass Spectrometry; Tissue Distribution

Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone.. Tumor volume progression was measured following treatment with both drugs as single agents, in combination, and at multiple doses. Pharmacokinetics in tumors and other tissues was also assessed. Pharmacodynamic interactions were evaluated quantitatively.. A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 mg/kg everolimus, alone and in combination, did not achieve significant tumor growth inhibition. Higher doses (20 mg/kg of sorafenib and 1 mg/kg of everolimus) inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination. Tumor volume progression was described by a linear growth model, and drug effects were described by Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs.. The results indicate that combinations of mTOR and multi-kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy.

Topics: Animals; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Synergism; Everolimus; Humans; Mice; Mice, SCID; Models, Biological; Molecular Targeted Therapy; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Malignant insulinoma is an infrequent functional endocrine tumor of the pancreas. Adequate therapy is a demanding challenge for oncologists and endocrinologists.. To evaluate the results of multidisciplinary management of malignant insulinoma.. Retrospective review of patients with malignant insulinoma treated from 1995 to 2011.. Seven patients with malignant insulinoma were included: four males and three females; median age was 61.8 years (range 37-78). Six tumors were sporadic and one was diagnosed in a patient with a type 1 multiple endocrine neoplasia (MEN-1). Surgery was performed in six cases and one patient was considered unresectable. Hypoglycemias persisted in all cases and somatostatin analogs, glucocorticoids and diazoxide were used. Two patients received everolimus. Other techniques were chemoembolization and internal radiation therapy with yttrium-90. Successful liver transplant was done in the patient with MEN-1.. Hypoglycemia management is complex and requires multiple therapies. Further evaluations will be necessary to determine the best treatment.

Topics: Adult; Aged; Chemoembolization, Therapeutic; Diazoxide; Everolimus; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Radiotherapy; Retrospective Studies; Sirolimus; Treatment Outcome; Vasodilator Agents; Yttrium Radioisotopes

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Rapamycin (RPM), a specific inhibitor of mTOR, exhibits potent and broad in vitro and in vivo antitumor activity against leukemia, breast cancer, and melanoma. Recent studies showing that RPM sensitizes cancers to chemotherapy and radiation therapy have attracted considerable attention. This study aimed to examine the radiosensitizing effect of RPM in vitro, as well as its mechanism of action. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay showed that 10 nmol/L to 15 nmol/L of RPM had a radiosensitizing effects on pancreatic carcinoma cells in vitro. Furthermore, a low dose of RPM induced autophagy and reduced the number of S-phase cells. When radiation treatment was combined with RPM, the PC-2 cell cycle arrested in the G2/M phase of the cell cycle. Complementary DNA (cDNA) microarray and reverse transcription polymerase chain reaction (RT-PCR) revealed that the expression of DDB1, RAD51, and XRCC5 were downregulated, whereas the expression of PCNA and ABCC4 were upregulated in PC-2 cells. The results demonstrated that RPM effectively enhanced the radiosensitivity of pancreatic carcinoma cells.

Topics: Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Gene Expression Profiling; Humans; Pancreatic Neoplasms; Radiation Tolerance; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Blood Glucose; Diazoxide; Everolimus; Humans; Hypoglycemia; Insulinoma; Octreotide; Pancreatic Neoplasms; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Neuroendocrine tumors of the gastroenteropancreatic tract remain a difficult array of neoplasia to treat. Treatment of advanced and metastatic gastroenteropancreatic neuroendocrine tumors has traditionally been difficult with few systemic treatment options. In 2011, two new targeted therapies, everolimus and sunitinib were approved for treatment of pancreatic neuroendocrine tumor. The approval of these agents led to an enhanced interest in exploring novel agents. This can be evidenced by the fact that this is the first year that ASCO assembled related abstracts under a separate title of neuroendocrine tumor. The annual American Society of Clinical Oncology (ASCO) conference in 2013 presented four abstracts (#4030, #4031, #4032, #4136) that shed light on new therapeutic options that help target the unique pathways involved in these neuroendocrine malignancies.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Everolimus; Humans; Indoles; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pyrroles; Sirolimus; Stomach Neoplasms; Sunitinib; Treatment Outcome

Neuroendocrine tumors of the pancreas (pNETs) are classified on the basis of their differentiation as well as the functional status. Current treatment options for non resectable disease include everolimus, sunitinib, somatostatin analogs and chemotherapy. A number of trials with novel compounds and drug combinations were reported at the recent ASCO Annual Meeting. Pasireotide is a novel somatostatin analog with broader affinity for the somatostatin receptors compared to the traditional octreotide and lantreotide and it appears to be safe in patients with pNETs according to a phase I study (Abstract #e15126). The combination of octreotide with everolimus showed promising response rate and progression free survival in a phase II study (Abstract #4136). In another phase II study, the AKT inhibitor MK-2206 was well tolerated with moderate efficacy (Abstract #e15133). Last but not least, we discuss the updated data from a phase II study that used the combination of temsirolimus with bevacizumab in patients with advanced pNETs (Abstract #4032).

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Everolimus; Heterocyclic Compounds, 3-Ring; Humans; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; Treatment Outcome

Chemotherapy-associated interstitial lung disease (ILD) is often fatal, and the chemotherapeutic regimen generally cannot be resumed. ILD associated with the mammalian target of rapamycin (mTOR) inhibitor everolimus has many features distinct from chemotherapy-associated ILD. We present the case of a 58-year-old woman with an advanced pancreatic neuroendocrine tumor with liver metastases, in whom everolimus treatment was maintained and resulted in a partial response despite two occurrences of everolimus-induced ILD during a 31-month treatment period until disease progression. Physicians treating with everolimus should monitor patients closely for ILD and should apply appropriate management strategies to optimize the possibility of maintaining everolimus therapy.

Topics: Antineoplastic Agents; C-Reactive Protein; Everolimus; Female; Humans; Liver Neoplasms; Lung Diseases, Interstitial; Middle Aged; Mucin-1; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Sirolimus; Tomography, X-Ray Computed

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

Topics: Adult; Aged; Bone Neoplasms; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestinal Neoplasms; Liver Neoplasms; Lutetium; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Safety; Sirolimus; Stomach Neoplasms; Survival Rate

Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133(+) pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating that the mTOR pathway functions to maintain cancer stem-like cells. Further, rapamycin had different effects on CD133(+) cells compared to cyclopamine which is an inhibitor of the Hedgehog pathway. Thus, the mTOR pathway has a distinct role although both pathways maintain pancreatic cancer stem cells. Therefore, mTOR might be a promising target to eliminate pancreatic cancer stem cells.

Topics: AC133 Antigen; Animals; Antigens, CD; Cell Line, Tumor; Cell Survival; Glycoproteins; Hedgehog Proteins; Humans; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells; Pancreatic Neoplasms; Peptides; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Veratrum Alkaloids

A 55-year-old woman presented to our hospital with a chief complaint of abdominal pain. Computed tomography (CT) revealed a massive tumor originating from the tail of the pancreas, with liver and lymph node metastasis. Percutaneous biopsy was performed and yielded a diagnosis of pancreatic neuroendocrine carcinoma. The patient underwent distal pancreatectomy, lateral segmentectomy of the liver, para-aortic lymph node dissection, and cytoreductive surgery for treatment of peritoneal dissemination. Octreotide was administered on post-operative day (POD) 3. Treatment with everolimus (10 mg/day) was initiated on POD 32. Stable disease according to the Response Evaluation Criteria in Solid Tumors( RECIST) was observed for 4 months, and the patient survived for a total of 9 months after surgery. Everolimus was tolerated safely and was effective for the treatment of pancreatic neuroendocrine carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Chemotherapy, Adjuvant; Everolimus; Fatal Outcome; Female; Humans; Middle Aged; Palliative Care; Pancreatic Neoplasms; Sirolimus

Everolimus targets the mammalian target of rapamycin, a kinase that promotes cell growth and proliferation in pancreatic cancer. Sorafenib inhibits the Raf-mitogen-activated protein kinase, vascular endothelial growth factor, and platelet-derived growth factor pathways, thus inhibiting cell growth and angiogenesis. Combinations of these two agents are under evaluation for therapy of several cancers. This study examined the effects of everolimus and sorafenib on proliferation of the pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Cell growth inhibition was evaluated in vitro for a range of concentrations of the drugs alone and in combination. Maximum inhibition capacity (I (max)) and potency (IC(50)) were determined. The data were analyzed to characterize drug interactions using two mathematical analysis techniques. The Ariens noncompetitive interaction model and Earp model were modified to accommodate alterations in the inhibition parameters of one drug in the presence of another. Sorafenib alone inhibited growth of both cell lines completely (I (max) = 1), with an IC(50) of 5-8 μM. Maximal inhibition by everolimus alone was only 40% (I (max) = 0.4) in both cell lines, with an IC(50) of 5 nM. Slight antagonistic interaction occurred between the drugs; both analytic methods estimated the interaction term Ψ as greater than 1 for both cell lines. The in vitro data for two pancreatic cancer cell lines suggest that a combination of these two drugs would be no more efficacious than the individual drugs alone, consistent with the drug interaction analysis that indicated slight antagonism for growth inhibition.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Interactions; Everolimus; Humans; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Sirolimus; Sorafenib

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or (177)Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Cell Line, Tumor; Disease Models, Animal; Everolimus; Humans; Male; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Sirolimus; TOR Serine-Threonine Kinases

Topics: Anti-Infective Agents; Brain Abscess; Everolimus; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Insulinoma; Middle Aged; Neoplasm Metastasis; Nocardia; Nocardia Infections; Pancreatic Neoplasms; Sirolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Administration, Oral; Angiogenesis Inhibitors; Antineoplastic Agents; Cost-Benefit Analysis; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Outcome Assessment, Health Care; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib

Everolimus is an mTOR inhibitor commonly used to treat metastatic pancreatic neuroendocrine tumors (pNETs) and renal cell carcinoma, and for posttransplant immunosuppression. This report presents a case of a 36-year-old man being treated with everolimus for a metastatic pNET who developed severe hypertriglyceridemia and acute pancreatitis. The incidence of hypertriglyceridemia reported in large prospective randomized trials is reviewed and the management of hypertriglyceridemic pancreatitis is discussed. Careful monitoring of triglyceride levels and dose adjustments of everolimus together with lipid-lowering therapy can allow patients to continue this medication. Because there are increasing indications for the use of everolimus, prescribing oncologists must be cognizant of the common and serious side effects.

Topics: Adult; Antineoplastic Agents; Everolimus; Humans; Hypertriglyceridemia; Male; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatitis; Sirolimus

While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs.. The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed.. The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05 ± 1.84% as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1.. Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high-grade gastroenteropancreatic neuroendocrine tumors.

Topics: Adult; Aged; Animals; Antineoplastic Agents; Cell Line, Tumor; Everolimus; Female; Humans; Intestinal Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Stomach Neoplasms; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The signaling pathways that mediate the development of pancreatic ductal adenocarcinoma (PDAC) downstream of mutant Kras remain incompletely understood. Here, we focus on ribosomal protein S6 (rpS6), an mTOR effector not implicated previously in cancer. Phosphorylation of rpS6 was increased in pancreatic acinar cells upon implantation of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or transgenic expression of mutant Kras. To examine the functional significance of rpS6 phosphorylation, we used knockin mice lacking all five phosphorylatable sites in rpS6 (termed rpS6(P-/-) mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6(P-/-) mice. The rpS6 mutants expressing oncogenic Kras showed increased p53 along with increased staining of γ-H2AX and 53bp1 (Trp53bp1) in areas of acinar ductal metaplasia, suggesting that rpS6 phosphorylation attenuates Kras-induced DNA damage and p53-mediated tumor suppression. These results reveal that rpS6 phosphorylation is important for the initiation of pancreatic cancer.

Topics: Animals; Base Sequence; DNA Damage; DNA Primers; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Pancreatic Neoplasms; Phosphorylation; Polymerase Chain Reaction; Ribosomal Protein S6; Sirolimus

Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Co-Repressor Proteins; DNA Helicases; Everolimus; Humans; Indoles; Molecular Chaperones; Mutation; Neuroendocrine Tumors; Nuclear Proteins; Pancreatic Neoplasms; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrroles; Sirolimus; Sunitinib; X-linked Nuclear Protein

Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option.. Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded.. Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1-35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia.. Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

Topics: Adult; Aged; Antineoplastic Agents; Everolimus; Female; Humans; Hypoglycemia; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Sirolimus; Treatment Outcome

Topics: Erlotinib Hydrochloride; Everolimus; Humans; Molecular Targeted Therapy; Pancreatic Neoplasms; Protein Kinase Inhibitors; Quinazolines; Sirolimus

Mammalian target of rapamycin (mTOR) is a giant protein kinase that controls cell proliferation, growth, and metabolism. mTOR is regulated by nutrient availability, by mitogens, and by stress, and operates through two independently regulated hetero-oligomeric complexes. We have attempted to identify the cellular components necessary to maintain the activity of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, using a whole genome approach involving RNAi-induced depletion of cellular polypeptides. We have used a pancreatic ductal adenocarcinoma (PDAC) cell line, Mia-PaCa for this screen; as with many pancreatic cancers, these cells exhibit constitutive activation of mTORC1. PDAC is the most common form of pancreatic cancer and the 5-year survival rate remains 3-5% despite current nonspecific and targeted therapies. Although rapamycin-related mTOR inhibitors have yet to demonstrate encouraging clinical responses, it is now evident that this class of compounds is capable of only partial mTORC1 inhibition. Identifying previously unappreciated proteins needed for maintenance of mTORC1 activity may provide new targets and lead to the development of beneficial therapies for pancreatic cancer.

Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Genome, Human; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Pancreatic Neoplasms; Phosphorylation; Proteins; Ribosomal Protein S6; RNA Interference; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transfection

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Doxorubicin; Humans; Irinotecan; Liver Neoplasms; Mice; Mice, Nude; Pancreatic Neoplasms; Prostheses and Implants; Sirolimus; Topotecan; Xenograft Model Antitumor Assays

Mammalian target of rapamycin complex 1 (mTORC1) is frequently activated in human cancers; however, clinical trials of rapalog (the mTORC1 inhibitors) have shown that pancreatic ductal adenocarcinomas (PDACs) resist to the treatment. Rapalog treatment activated the extracellular signal-regulated kinase (ERK) pathway in K-Ras mt PDAC cells. K-Ras knockdown abolished the insulin-like growth factor-1 (IGF-1)-induced ERK pathway in the K-Ras mt PDAC cells and enhanced the therapeutic efficacy of everolimus in treating K-Ras mt PDAC cells-derived mouse xenografts. The results indicate that targeting of K-Ras mutation may lead to the development of therapies that overcome rapalog resistance in PDAC.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Female; Humans; Insulin-Like Growth Factor I; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Mutation; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Pyrroles; ras Proteins; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Everolimus; Famous Persons; Humans; Indoles; Liver Neoplasms; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Pyrroles; Risk Factors; Sirolimus; Sunitinib

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; World Health Organization

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Gastrointestinal Neoplasms; Humans; Indoles; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Pyrroles; Sirolimus; Somatostatin; Sunitinib

Malignancy is not uncommon with immunosuppressive therapy, but pancreatic cancer is infrequently complicated in recipients of heart transplantation. Here we report a transplant case diagnosed with pancreatic cancer 4 years and 8 months after the heart transplantation. We changed the immunosuppressive regimen after the malignancy was detected, and administered everolimus along with chemotherapy using S-1, an oral fluoropyrimidine prodrug. The patient lived for 8 months after the diagnosis, and received metallic stenting for the biliary and duodenal obstruction. Also, to the best of our knowledge, this is the first report about chemotherapy and endoscopic intervention for pancreatic cancer in a heart transplantation patient.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Cholestasis, Extrahepatic; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Duodenal Obstruction; Everolimus; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Ischemia; Neoplasm Staging; Oxonic Acid; Pancreatic Neoplasms; Postoperative Complications; Sirolimus; Stents; Tegafur

Pancreatic cancer is a relatively rare malignancy with a very aggressive natural course, not restrained by the existing current treatments. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of few phase I clinical studies on solid tumors and pancreatic cancer were presented. In particular, in the field of immunotherapy, a pilot phase I study tested for first time a carcinoembryonic antigen (CEA)-based vaccine (Abstract #2561) on patients with pancreatic adenocarcinoma and another one the optimal dose and efficacy of trabedersen, an inhibitor of tissue growth factor-beta 2 (TGF-β2) aiming to enhance antitumor immune responses (Abstract #4034). Other phase I studies explored the pharmacokinetic and pharmacodynamic properties of an oral gemcitabine pro-drug (LY2334737; Abstract #2554), or of the combination of gemcitabine with sirolimus (Abstract #3096) or the combination of gemcitabine with an inhibitor of mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK) (MEK 1/2; Abstract #4034).

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Deoxycytidine; Gemcitabine; Humans; Immunotherapy; Neoplasms; Pancreatic Neoplasms; Sirolimus

Everolimus, an inhibitor of the mammalian target of rapamycin, has recently demonstrated efficacy and safety in a Phase III, double-blind, randomized trial (RADIANT-3) in 410 patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumours. Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival, representing a 65% risk reduction for progression. The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study.. Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17). The primary endpoint was progression-free survival. Safety was evaluated on the basis of the incidence of adverse drug reactions.. Progression-free survival was significantly prolonged with everolimus compared with placebo. The median progression-free survival was 19.45 months (95% confidence interval, 8.31-not available) with everolimus vs 2.83 months (95% confidence interval, 2.46-8.34) with placebo, resulting in an 81% risk reduction in progression (hazard ratio, 0.19; 95% confidence interval, 0.08-0.48; P< 0.001). Adverse drug reactions occurred in all 23 (100%) Japanese patients receiving everolimus and in 13 (77%) patients receiving placebo; most were grade 1/2 in severity. The most common adverse drug reactions in the everolimus group were rash (n = 20; 87%), stomatitis (n = 17; 74%), infections (n = 15; 65%), nail disorders (n = 12; 52%), epistaxis (n = 10; 44%) and pneumonitis (n = 10; 44%).. These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours.

Topics: Adult; Aged; Aged, 80 and over; Clinical Trials, Phase III as Topic; Double-Blind Method; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Sirolimus; Survival Rate; Young Adult

Everolimus (Afinitor) and sunitinib (Sutent) were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). (Afinitor is a registered trademark of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Sutent is a registered trademark of Pfizer Inc., New York, NY, USA.) This analysis examined the projected cost-effectiveness of everolimus vs sunitinib in this setting from a US payer perspective.. A semi-Markov model was developed to simulate a cohort of patients with advanced, progressive pNET and to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) gained when treating with everolimus vs sunitinib. Efficacy data were based on a weight-adjusted indirect comparison of the agents using phase 3 trial data. Model health states included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Therapy costs were based on wholesale acquisition cost. Other costs such as physician visits, tests, hospitalizations, and adverse event costs were obtained from literature and/or primary research. Utility inputs were based on primary research. Sensitivity analyses were conducted to test the model's robustness.. In the base-case analysis, everolimus was associated with an incremental 0.448 LYG (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained). The ICER fell within the cost per QALY range for many widely used oncology drugs. Sensitivity analyses demonstrated that, overall, there is a trend that everolimus is cost-effective compared to sunitinib in this setting.. Results of the indirect analysis were not statistically significant (p > 0.05). Assumptions that treatment patterns are the same across therapies may not represent real-world practice.. While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies, everolimus is expected to be cost-effective relative to sunitinib in advanced, progressive pNET.

Topics: Antineoplastic Agents; Cost-Benefit Analysis; Disease Progression; Drug Costs; Everolimus; Humans; Indoles; Markov Chains; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Quality-Adjusted Life Years; Sirolimus; Sunitinib; Survival Analysis; United States

The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer.. Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated.. Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression.. SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.

Topics: Animals; Cell Line, Tumor; Chemokine CXCL12; Cyclin D1; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Pyridines; Quinazolines; Receptors, CXCR; Receptors, CXCR4; RNA Interference; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Pancreatic neuroendocrine tumors (pNET), also known as islet cell tumors, exhibit a wide range of biologic behaviors ranging from long dormancy to rapid progression. Currently, there are few molecular biomarkers that can be used to predict recurrence/metastasis or response to therapy. This study examined the predictive and prognostic value of a single nucleotide polymorphism substituting an arginine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain. We established the FGFR4 genotype of 71 patients with pNETs and correlated genotype with biologic behavior. We created an in vivo model of pNET with BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to examine response to the mTOR inhibitor everolimus. We then validated the predictive results of experimental studies in a group of patients treated with everolimus. FGFR4-R388 is associated with more aggressive clinical behavior in patients with pNETs with a statistically significant higher risk of advanced tumor stage and liver metastasis. Using an orthotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intraperitoneal spread and metastatic growth within the liver. Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsiveness to everolimus. Concordantly, there was a statistically significant reduction in response to everolimus in patients with FGFR4-R388. Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predictive marker of potential therapeutic importance in this disease.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Cell Growth Processes; Cell Line, Tumor; Disease Progression; Everolimus; Female; Humans; Male; Mice; Mice, SCID; Middle Aged; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Receptor, Fibroblast Growth Factor, Type 4; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Young Adult

Rapamycin (Rapa), an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. This study aims to investigate the effects of Rapa suppressing proliferation of pancreatic carcinoma PC-2 cells in vitro and its molecular mechanism involved in antitumor activities. MTT assays showed that the inhibition of proliferation of PC-2 cells in vitro was in a time- and dose-dependent manner. By using transmission electron microscopy, apoptosis bodies and formation of abundant autophagic vacuoles were observed in PC-2 cells after Rapa treatment. Flow cytometry assays also showed Rapa had a positive effect on apoptosis. MDC staining showed that the fluorescent density was higher and the number of MDC-labeled particles in PC-2 cells was greater in the Rapa treatment group than in the control group. RT-PCR revealed that the expression levels of p53, Bax and Beclin 1 were up-regulated in a dose-dependent manner, indicating that Beclin 1 was involved in Rapa induced autophagy and Rapa induced apoptosis as well as p53 up-regulation in PC-2 cells. The results demonstrated that Rapa could effectively inhibit proliferation and induce apoptosis and autophagy in PC-2 cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; bcl-2-Associated X Protein; Beclin-1; Cadaverine; Cell Line, Tumor; Cell Proliferation; Cell Shape; Flow Cytometry; Humans; Membrane Proteins; Mice; NIH 3T3 Cells; Pancreatic Neoplasms; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases; Vacuoles

Long-term stabilization of advanced renal cell carcinoma (RCC) by the sequence of sorafenib monotherapy followed by sunitinib and everolimus treatments in a man with multiple metastases is reported. A 66-year-old man was diagnosed with advanced RCC in 2005. The patient initially underwent nephrectomy, but subsequently the disease metastasized to the lung, lymph nodes, and pancreas. The patient received sorafenib 400 mg bid in a clinical trial. He experienced minimal and manageable adverse events and achieved stable disease (SD), which was maintained with sorafenib therapy for nearly 3 years before the development of liver metastases. The patient was then prescribed sunitinib, with which he also experienced SD for 1.2 years until disease progression prompted the initiation of third-line everolimus therapy, resulting in SD for another 8 months. The patient lived with stabilized RCC for 4.6 years with the use of these three sequential targeted therapies. First-line sorafenib monotherapy achieved a durable stable response and subsequent use of sunitinib and then everolimus permitted a return to SD after disease progression. The patient experienced minimal toxicity from the regimen, suggesting that it can be safely administered to elderly patients.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Everolimus; Humans; Indoles; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib

Topics: AMP-Activated Protein Kinase Kinases; Antineoplastic Agents; Base Sequence; Everolimus; Humans; Male; Middle Aged; Mutation; Pancreatic Neoplasms; Peutz-Jeghers Syndrome; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Disease Progression; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrroles; Quality of Life; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Neuroendocrine tumors of pancreas (PNET) are very rare, consisting of heterogeneous histological subtypes with a variable natural history and different clinical manifestations. Although the vast majority of these neoplasms are sporadic, it is possible to be part of a genetic syndrome such as multiple endocrine neoplasia 1 (MEN-1) or tuberous sclerosis (TSC). When systemic treatment is required the options are limited and management strategy is generally based on experts' consensus or clinical experience. The prognosis is usually better than in pancreatic adenocarcinoma, though poorly differentiated PNET behave aggressively and survival is shortened. Since last year, there has been a significant advance in the management of PNET, after reported data confirmed the efficacy of everolimus, an mTOR inhibitor, in patients with advanced disease. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Symposium, updated results of the phase III trial (RADIANT-3) regarding the efficacy of everolimus in PNET (Abstract #158) were reported, along with the results of a subgroup analysis of the Japanese patients enrolled in this study (Abstract #289). Another agent with promising activity in PNET which will be discussed in this review is sunitinib, a biological agent with multikinase inhibitor properties (Abstract #244).

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Everolimus; Humans; Immunosuppressive Agents; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome

Topics: Animals; Clinical Trials, Phase III as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Everolimus; Humans; Indoles; Mice; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Signal Transduction; Sirolimus; Sunitinib; Survival Rate; Translational Research, Biomedical

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Data Interpretation, Statistical; Disease-Free Survival; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Off-Label Use; Pancreatic Neoplasms; Pyrroles; Randomized Controlled Trials as Topic; Rare Diseases; Signal Transduction; Sirolimus; Sunitinib; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; United States

Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms.. Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹⁸F-FDG uptake was quantified as the maximum standardized uptake value.. All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹⁸F-FDG uptake. Everolimus reduced tumor and muscle ¹⁸F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%.. Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Blood Glucose; Everolimus; Female; Fluorodeoxyglucose F18; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Positron-Emission Tomography; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Blood Glucose; Diabetes Complications; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib

Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 ± 1.6 g vs. 29.3 ± 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 ± 8 ng/mL vs. 199 ± 11 ng/mL; P = 0.0006) and leptin (1.14 ± 0.2 ng/mL vs. 5.05 ± 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 ± 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 ± 206 mm(3); P = 0.04) relative to controls (550 ± 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki-67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3β, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer.

Topics: Animals; Antibiotics, Antineoplastic; Blotting, Western; Body Weight; Caloric Restriction; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Disease Models, Animal; Glucose; Glucose Tolerance Test; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunoenzyme Techniques; Insulin-Like Growth Factor I; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Survival; Diabetes Mellitus, Type 1; Gene Expression Regulation; Genes, Dominant; Hepatocyte Nuclear Factor 1-alpha; Insulin-Secreting Cells; Insulinoma; Leucine; Mutation; Pancreatic Neoplasms; Protein Processing, Post-Translational; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease Models, Animal; Everolimus; Humans; Indoles; Mice; Pancreatic Neoplasms; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Pancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy.. Using a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively), whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI) resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity.. Notch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made previously. Furthermore, we discovered that this regulation is dependent on RhoA/Rock1 activation. Enhanced phospho-Akt suppression when GSI is combined with rapamycin suggests that targeting both pathways will lead to a greater efficacy in the treatment of patients with pancreas cancer.

Topics: Amyloid Precursor Protein Secretases; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Female; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; PTEN Phosphohydrolase; Receptors, Notch; Signal Transduction; Sirolimus

Inhibition of mTORC1 with the mTOR inhibitor rapamycin may lead to an induction of Akt phosphorylation in cancer cells via mTORC2 activation. Using gastric and pancreatic cancer cells, we further investigated this paradoxical signaling response and found that rapamycin additionally up-regulates both IGF-IR and Her2 expression. Using RNAi for down-regulating RICTOR, this induction of receptor kinase expression was identified to be mediated via an mTORC2-induced Akt activation. Moreover, mTORC2 inhibition reduced the phosphorylation of GSK-3 and NF-kappaB, and significantly impaired cancer cell motility. In conclusion, inhibition of mTORC2 may abrogate unfavorable signaling effects of mTOR inhibitors, hence providing a novel rationale for therapy.

Topics: Blotting, Western; Carrier Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glycogen Synthase Kinase 3; Humans; NF-kappa B; Pancreatic Neoplasms; Phosphorylation; Rapamycin-Insensitive Companion of mTOR Protein; Receptor, ErbB-2; Receptor, IGF Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Sirolimus; Stomach Neoplasms; Transcription Factors

Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy.. We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support.. Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor.. Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases.. Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.

Topics: Aged; Everolimus; Humans; Hypoglycemia; Insulinoma; Liver Neoplasms; Male; Middle Aged; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Sirolimus

To investigate the effect of immunosuppression agent Everolimus on the viability and function of insuloma cells (INS-1) and pancreatic islet cells cultured in vitro.. INS-1 cells and islets were treated with a series of concentrations of immunosuppression agents (Everolimus, Cyclosporin A, Sirolimus and Mycophenolate Mofetil). The viability of INS-1 cells and rat pancreatic islets were determined with MTT and the function of INS-1 cells and rat pancreatic islets was evaluated with Glucose-stimulated insulin secretion assay.. Above the clinical blood concentration, the inhibition rate of islet cell proliferation in the high concentration group of Everolimus and Sirolimus was significantly lower than that of Cyclosporin A and Mycophenolate Mofetil group (P < 0.05); Everolimus in the blood drug level, like other immunosuppressive agents, can inhibit the function of insulin secretion, and the stimulation index of each group was no significant difference.. Compared to Mycophenolate Mofetil and Cyclosporin A, Everilimus and Sirolimus demonstrate lower toxicity effect on INS-1 cells and rat pancreatic islets in vitro and Everolimus is expected as a new type of immunosuppressive agent used in clinical islet transplantation.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Cyclosporine; Everolimus; Immunosuppressive Agents; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Mycophenolic Acid; Pancreatic Neoplasms; Rats; Sirolimus

Human cervical cancer oncoprotein 1 (HCCR-1), reported as a negative regulator of p53, is over-expressed in a variety of human cancers. However, it is yet unknown whether HCCR-1 plays any role in pancreatic cancer development. The aim of this study was to investigate the effect of epidermal growth factor on the expression of HCCR in pancreatic cancer cells, and to explore if PI3K/Akt/mTOR signaling pathway mediated this expression.. A polyclonal antibody against HCCR protein was raised by immunizing Balb/c mice with the purified recombinant protein pMBPc-HCCR. Tissue samples were constructed on a tissue chip, and the expression of HCCR was investigated by immunohistochemistry assay and Western blotting. Pancreatic cell line, PANC-1 cells were stably transfected with plasmids containing sense-HCCR-1 fragment and HCCR siRNA fragment. MTT and transwell assay were used to investigate the proliferation and invasion of stable tansfectants. The specific inhibitor of PI3K and mTOR was used to see if PI3K/mTOR signal transduction was involved in the induction of HCCR gene expression. A Luciferase assay was used to see if Akt can enhance the HCCR promoter activity.. HCCR was up-regulated in pancreatic tumor tissues (mean Allred score 4.51+/-1.549 vs. 2.87+/-2.193, P<0.01), especially with high expression in poorly differentiated pancreatic cancer. The growth of cells decreased in HCCR-1 siRNA transfected cells compared with vector transfectants. The number of invasion cells was significantly lower in HCCR-1 siRNA transfected cells (24.4+/-9.9) than that in vector transfectants (49.1+/-15.4). Treatment of PANC-1 cells with epidermal growth factor increased HCCR protein level in a dose- and time-dependent manner. However, application of LY294002 and rapamycin caused a dramatic reduction of epidermal growth factor-induced HCCR expression. Over-expression of exogenous constitutively active Akt increased the HCCR promoter activity; in contrast, dominant negative Akt decreased the promoter activity.. EGF-induced HCCR-1 over-expression is mediated by PI3K/AKT/mTOR signaling which plays a pivotal role in pancreatic tumor progression, suggesting that HCCR-1 could be a potential target for cancer therapeutics.

Topics: Animals; Antibodies; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromones; Epidermal Growth Factor; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Morpholines; Neoplasm Invasiveness; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Promoter Regions, Genetic; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Recombinant Proteins; RNA Interference; Signal Transduction; Sirolimus; Time Factors; Tissue Array Analysis; TOR Serine-Threonine Kinases; Transfection; Up-Regulation

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Cytotoxins; Embolization, Therapeutic; Europe; Female; Follow-Up Studies; Gastrointestinal Neoplasms; General Surgery; Humans; Incidence; Interferon-alpha; Male; Neoplasm Metastasis; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Risk Assessment; Sirolimus; Somatostatin; Survival Analysis; Treatment Outcome

The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic.. Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs).. In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects.. Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker.

Topics: Adenocarcinoma; Adult; Aged; Antibiotics, Antineoplastic; Female; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET.. Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics.. Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy.. Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Survival; Clinical Trials, Phase II as Topic; Disease Models, Animal; ErbB Receptors; Erlotinib Hydrochloride; Humans; Immunohistochemistry; Immunosuppressive Agents; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Quinazolines; Repressor Proteins; RNA Interference; Signal Transduction; Sirolimus; Survival Analysis; Survivin; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Disease Models, Animal; ErbB Receptors; Erlotinib Hydrochloride; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Quinazolines; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome

Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.. Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo.. RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro.. Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.

Topics: Animals; Antineoplastic Agents; Bromodeoxyuridine; Cell Cycle; Cell Line, Tumor; Diphenylamine; Enzyme Inhibitors; Humans; Male; MAP Kinase Kinase Kinases; Mice; Neoplasm Transplantation; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Sulfonamides

This is a report of a 61-year-old woman with improved pulmonary arterial hypertension following treatment with rapamycin for an islet cell tumor of the pancreas with liver metastases.

Topics: Antibiotics, Antineoplastic; Electrocardiography; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Sirolimus; Tomography, X-Ray Computed

Topics: Adult; Aged; Blood Glucose; Everolimus; Female; Humans; Hypoglycemia; Immunosuppressive Agents; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Sirolimus; Young Adult

Over-expression of eIF4E indicates a poor prognosis in different tumors. In the present study, we investigated the frequency of eIF4E, 4E-BP1 and phosphorylated 4E-BP1 expression in PDAC cell lines, gastric carcinoma (GC) cell lines and human embryonic pancreatic cells, as well as gene therapy using translation repressor gene 4E-BP1 in combination with the mTOR inhibitor rapamycin. We also assessed the significance of eIF4E expression in 80 PDAC cases. Combination therapy of adenovirus vector-delivered 4E-BP1 gene and rapamycin was administered to determine their growth inhibition effect in vitro and in vivo in mice. Our study revealed that all PDAC cell lines, GC cell lines and human embryonic pancreas-derived cells expressed the 25-kDa eIF4E protein (MIAPaca-2 cells also expressed the 13-kDa protein 4E-BP1). The 80 PDAC specimens showed a heterogeneous pattern of eIF4E staining. No significant correlation between eIF4E expression and TNM classification was found. Adenovirus vectors Ad-4E-BP1 and Ad-GFP efficiently showed transgenic expression with hyperphosphorylation of 4E-BP1; however, insignificant growth inhibition of the PDAC and GC cell lines was observed. Combination therapy with rapamycin significantly inhibited proliferation and tumor growth in vitro as well as in vivo. Therefore, combination of Ad 4E-BP1 and rapamycin may be a more effective adjuvant therapy.

Topics: Adaptor Proteins, Signal Transducing; Adenoviridae; Adult; Aged; Aged, 80 and over; Animals; Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Proliferation; Combined Modality Therapy; Female; Genetic Therapy; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Pancreatic Neoplasms; Phosphoproteins; Sirolimus; Transduction, Genetic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities.. We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population.. Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival.. The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.

Topics: AC133 Antigen; Animals; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Female; Gemcitabine; Glycoproteins; Hedgehog Proteins; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplastic Stem Cells; Pancreatic Neoplasms; Peptides; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Veratrum Alkaloids

Insulinomas are rare tumors of the pancreatic islet cells that produce insulin. Approximately 5 to 10% of these tumors are cancerous, and control of insulin secretion and hypoglycemia may be difficult in these patients. Malignant insulinomas generally respond poorly to traditional chemotherapeutic agent regimens. At present, streptozotocin is the only approved drug for the treatment of pancreatic islet cell tumors. SETTING AND PATIENT: This report describes a case of an elderly gentleman with a metastatic pancreatic insulinoma and severe hypoglycemia. A continuous infusion of octreotide lowered the blood glucose levels further. He required diazoxide, a thiazide diuretic, phenytoin, and a constant infusion of glucose to control the hypoglycemia and elevated insulin levels.. Rapamycin was administered at an oral dose of 2 mg/d.. On the mTOR (mammalian target of rapamycin) agent rapamycin, he was weaned off all drugs except for the thiazide diuretic and maintained euglycemia with a reduction of circulating insulin levels. He remained euglycemic for the past year with no evidence of tumor progression based on Octreoscan. His quality of life is excellent, and he remains active having recently completed a triathlon.. Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant beta-cell growth and proliferation as well as inhibiting insulin production.

Topics: Adenoma, Islet Cell; Aged; Aged, 80 and over; Humans; Hydrochlorothiazide; Hypoglycemia; Male; Pancreatic Neoplasms; Sirolimus; Streptozocin

Treating patients with metastatic carcinoma of the pancreas can lead to regression of disease, but the tumor becomes resistant to therapy within a few months. If resistance can be reversed or prevented, the chemotherapeutic benefit may be prolonged.. Two patients with metastatic pancreatic cancer progressed on gemcitabine, capecitabine and docetaxel (GTX). When sirolimus was added to this regimen at a dosage to achieve a serum level of at least 10 ng/dL at the time of the gemcitabine and docetaxel infusion, their tumors regressed.. This demonstrates that the addition of sirolimus to a gemcitabine/docetaxel containing regimen can reverse tumor resistance in the clinical setting.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fatal Outcome; Female; Fluorouracil; Gemcitabine; Humans; Male; Pancreatic Neoplasms; Sirolimus; Treatment Outcome

We have generated an EL1-luc/TAg transgenic mouse model that develops spontaneous and bioluminescent acinar cell carcinomas. We applied this model to noninvasively monitor tumor development and drug response.. EL1-luc/TAg transgenic mice of 11 weeks of age were treated with rapamycin (5 mg/kg, i.p.) or vehicle for 6 to 12 weeks. Tumor development was monitored through bioluminescence imaging and necropsy at the study end point.. EL1-luc/TAg transgenic mice showed pancreas-specific bioluminescence signal before tumor progression and produced increasing light emission from the onset of the pancreatic acinar cell carcinomas. The latency of tumor development ranged from 10 to >20 weeks of age in these mice. Progression of the primary acinar cell carcinoma was accompanied by emergence of metastatic lesions in the abdominal organs, including liver and gastrointestinal fat tissues. Rapamycin treatment suppressed tumor development.. The EL1-luc/TAg mouse provides a noninvasive approach for monitoring spontaneous acinar cell carcinoma development and comprises a convenient tool for the evaluation of novel therapeutics against pancreatic cancers. Tumor growth suppression through inhibition of the mammalian target of rapamycin pathway further validates this model as clinically relevant.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Acinar Cell; Disease Models, Animal; Drug Monitoring; Longitudinal Studies; Luminescent Measurements; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Sirolimus

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The ERK and mTOR pathways show multiple interconnections that coordinate growth activation and the regulation of protein translation. Although drugs that target these pathways appear to have limited anti-cancer effects as single agents, we hypothesized that the monotherapy anticancer efficacy of these agents could be enhanced by their combination. The MEK inhibitor AZD6244 (ARRY-142886) and the mTOR inhibitor rapamycin were tested as single agents and in combination, using BxPC-3 and MIA PaCa-2 pancreatic cancer models in vivo. In both models, S6 ribosomal protein was almost completely inhibited with combined treatment, but only partially inhibited with the single agents. In addition, 48 h treatment with the drug combination produced greater apoptosis, revealed by caspase 3 cleavage, and growth inhibition measured using bromodeoxyuridine incorporation, compared to the single agents. AZD6244 but not rapamycin exhibited a significant anti-angiogenic effect, as shown by tumor VEGF ELISA assay and CD31 analysis. Plasma and tumor pharmacokinetic analyses indicated that AZD6244 accumulates in tumor tissue at concentrations that produce target inhibition and cell cycle arrest in vitro. In chronic dosing experiments, the drug combination was well tolerated, and showed greater growth inhibition compared to the single agents. These results are consistent with the hypothesis that ERK and mTOR signaling interact at multiple levels to regulate tumor growth in vivo, and support the testing of MEK plus mTOR inhibitor combinations in pancreatic cancer patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Cycle; Cell Line, Tumor; Drug Synergism; Flow Cytometry; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, SCID; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Pathologic; Pancreatic Neoplasms; Phosphorylation; Protein Serine-Threonine Kinases; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

SIMCA classification can be applied to 2D-PAGE maps to identify changes occurring in cellular protein contents as a consequence of illnesses or therapies. These data sets are complex to treat due to the large number of proteins detected. A method for identifying relevant proteins from SIMCA discriminating powers is proposed, based on the Box-Cox transformation coupled to probability papers. The method successfully allowed the identification of the relevant spots from 2D maps.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Electrophoresis, Gel, Two-Dimensional; Endothelium; Humans; Hydroxamic Acids; Mice; Neoplasms; Neuroblastoma; Pancreas; Pancreatic Neoplasms; Probability; Proteins; Proteomics; Sirolimus; Statistical Distributions; Vinblastine

Rapamycin inhibits the growth of several tumors including pancreatic carcinoma both in vitro and in vivo. The antitumor effects of FTY720 were also shown recently. The present study was performed to investigate the in vitro antiproliferative capacity of combined treatment with rapamycin and FTY720 on pancreatic cacinoma cell lines.. The Panc-1 and AsPc-1 cell lines were employed as the pancreatic carcinoma model in vitro. For monotreatment experiments, rapamycin was added in increasing doses from 0.002 micromol/L to 200 micromol/L; FTY720 was used from 1 micromol/L to 15 micromol/L. For combined treatment, two concentrations of rapamycin were combined with seven concentrations of FTY720; or two concentrations of FTY720 with five concentrations of rapamycin. The antiproliferative capacity was assessed by the MTT assay.. Rapamycin and FTY720 inhibited MTT incorporation into Panc-1 and AsPc-1 in dose-dependent fashion with or without serum stimulation. In coincubation experiments, great susceptibility to rapamycin was seen when combined with 10 micromol/L FTY720. An effective combination for AsPc-1 was 10 micromol/L FTY720 with 0.002 micromol/L rapamycin, resulting in more than 50% inhibition of MTT incorporation, and for Panc-1, 10 micromol/L FTY720 with 0.002 micromol/L rapamycin and 10 micromol/L FTY720 with 20 micromol/L rapamycin; the corresponding inhibition levels reached about 40% and 60%, respectively.. Rapamycin and FTY720 showed dose-dependent antiproliferative effects on pancreatic carcinoma cell lines in vitro both alone and in combination. The combined use of rapamycin and FTY720 showed additive and supra-additive antiproliferative effects on pancreatic carcinoma cell lines. The susceptibility of pancreatic carcinoma cells to rapamycin was significantly enhanced when combined with FTY720.

Topics: Cell Division; Cell Line, Tumor; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Pancreatic Neoplasms; Propylene Glycols; Sirolimus; Sphingosine

Topics: Antineoplastic Agents; Brachytherapy; Carcinoma, Renal Cell; Clinical Trials as Topic; Deoxycytidine; Endometrial Neoplasms; Everolimus; Female; Gemcitabine; Humans; Kidney Neoplasms; Male; Pancreatic Neoplasms; Sirolimus

Tumor hypoxia is an obstacle to radiotherapy. Radiosensitivity under hypoxic conditions is determined by molecular oxygen levels, as well as by various biological cellular responses. The insulin-like growth factor (IGF) signaling pathway is a widely recognized survival signal that confers radioresistance. However, under hypoxic conditions the role of IGF signaling in radiosensitivity is still poorly understood. Here, we demonstrate that IGF-II stimulation decreases clonogenic survival under hypoxic conditions in the pancreatic cancer cell lines AsPC-1 and Panc-1, and in the human breast cancer cell line MCF-7. IGF treatment under hypoxic conditions suppressed increased radiation sensitivity in these cell lines by pharmacologically inhibiting the phosphoinositide 3-kinase-mammalian target of rapamycin pathway, a major IGF signal-transduction pathway. Meanwhile, IGF-II induced the endoplasmic reticulum stress response under hypoxia, including increased protein levels of CHOP and ATF4, mRNA levels of CHOP, GADD34, and BiP, as well as splicing levels of XBP-1. The response was suppressed by inhibiting phosphoinositide 3-kinase and mammalian target of rapamycin activity. Overexpression of CHOP in AsPC-1 cells increased radiation sensitivity by IGF-II simulation under hypoxic conditions, whereas suppression of CHOP expression levels with small hairpin RNA or a dominant negative form of a proline-rich extensin-like receptor protein kinase in hypoxia decreased IGF-induced radiosensitivity. IGF-induced endoplasmic reticulum stress contributed to radiosensitization independent of cell cycle status. Taken together, IGF stimulation increased radiosensitivity through the endoplasmic reticulum stress response under hypoxic conditions.

Topics: Cell Hypoxia; Cell Line, Tumor; Endoplasmic Reticulum; Humans; Insulin-Like Growth Factor II; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Radiation Tolerance; Recombinant Proteins; Signal Transduction; Sirolimus

Nanotechnology has enabled significant advances in the areas of cancer diagnosis and therapy. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic formulations of poorly water-soluble, yet potent anticancer drugs. Whereas a number of nanoparticle-drug combinations are at various stages of preclinical or clinical assessment, the overwhelming majorities of such systems are injectable formulations and are incapable of being partaken orally. The development of an oral nano-delivery system would have distinct advantages for cancer chemotherapy. We report the synthesis and physicochemical characterization of orally bioavailable polymeric nanoparticles composed of N-isopropylacrylamide, methylmethacrylate, and acrylic acid in the molar ratios of 60:20:20 (designated NMA622). Amphiphilic NMA622 nanoparticles show a size distribution of <100 nm (mean diameter of 80 +/- 34 nm) with low polydispersity and can readily encapsulate a number of poorly water-soluble drugs such as rapamycin within the hydrophobic core. No apparent systemic toxicities are observed in mice receiving as much as 500 mg/kg of the orally administered void NMA622 for 4 weeks. Using NMA622-encapsulated rapamycin ("nanorapamycin") as a prototype for oral nano-drug delivery, we show favorable in vivo pharmacokinetics and therapeutic efficacy in a xenograft model of human pancreatic cancer. Oral nanorapamycin leads to robust inhibition of the mammalian target of rapamycin pathway in pancreatic cancer xenografts, which is accompanied by significant growth inhibition (P < 0.01) compared with control tumors. These data indicate that NMA622 nanoparticles provide a suitable platform for oral delivery of water-insoluble drugs like rapamycin for cancer therapy.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Design; Humans; Kinetics; Mice; Nanoparticles; Neoplasm Transplantation; Pancreatic Neoplasms; Polymers; Sirolimus; Technology, Pharmaceutical

The in vitro efficacy of both EGFR inhibitor gefitinib and mTor inhibitor rapamycin, either administrated alone or in different combination schedules, was analysed in four pancreas cancer cell lines. Both drugs were found to induce cell growth inhibition, apoptosis as well as a slight but stable accumulation of cells in the G0/G1 phase. In all cell lines, neither gefitinib nor rapamycin affected EGFR and the expression of its downstream effectors. By contrast, gefitinib inhibited in a fast and completely way p-EGFR and partially p-Akt while a 3 days-rapamycin exposure resulted in the inhibition of the expression of both mTor and p70S6K. Moreover, after early stimulation, the mTor inhibitor produced a progressive, and almost complete inhibition of p-Akt. The analysis of combined gefitinib and rapamycin administration showed a clear schedule-dependent activity which turned out to be synergic only when gefitinib was given before rapamycin. This synergism seemed to depend on increase of both p-Akt and p70S6K inhibition, the greater the induction of apoptosis, the higher the decrease in cell cycle rate. Moreover, the antiangiogenic activity of the two drugs given in combination was demonstrated by a strong reduction of VEGF release which turned out to be more pronounced in the synergic schedule, and HIF-1alpha inhibition-independent. Our results suggest that the schedule of gefitinib followed by rapamycin, acting at different levels of the EGFR cellular pathway, could induce antitumor and antiangiogenic effects of clinical interest in the pancreas cancer model.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Synergism; ErbB Receptors; Gefitinib; Humans; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth.. Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 x 2 or 5 x 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy.. A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (-16%), CT-26 (-70%), and human umbilical vascular endothelial cells (HUVEC; -72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (-83%), L3.6pl (-8%), and CT-26 (-82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (-57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 x 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm(3) versus 1144 mm(3); CT-26: 210 mm(3) versus 636 mm(3); P < 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy.. Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.

Topics: Angiogenesis Inhibitors; Animals; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Endothelium, Vascular; Everolimus; Humans; Mice; Microcirculation; Pancreatic Neoplasms; Radiation-Sensitizing Agents; Sirolimus

At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross antitumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit.

Topics: Adenocarcinoma; Animals; Biopsy, Fine-Needle; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pancreatic Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Quinazolines; Sirolimus; Xenograft Model Antitumor Assays

Tumors exhibiting constitutively activated PI(3)K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3)K/Akt/mTOR signaling.. BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation.. RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis.. In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Neuroectodermal Tumors; Pancreatic Neoplasms; Sirolimus

Topics: Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Humans; Male; Orphan Drug Production; Pancreatic Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Multiple lines of evidence support the existence of crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling systems. However, the precise molecular mechanism(s) mediating this interaction is poorly understood. The results presented in this study show that exposure of ductal pancreatic adenocarcinoma BxPc-3, HPAF-II, and PANC-1 cells to insulin for as little as 1 min rapidly enhanced the magnitude and the rate of increase in intracellular Ca2+ concentration produced by the GPCR agonists bradykinin, angiotensin II, vasopressin, neurotensin, and bombesin. The potentiating effect of insulin was dose dependent, and it was produced in response to Gq protein-coupled, but not Gi protein-coupled, receptor agonists. Real-time imaging of single cells showed that treatment with insulin enhances the rate and magnitude of phosphatidylinositol 4,5-bisphosphate hydrolysis and generation of inositol 1,4,5-trisphosphate in response to GPCR stimulation. Short-term treatment with rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, completely abrogated the ability of insulin to increase the rate and magnitude of Ca2+ signaling and production of inositol 1,4,5-trisphosphate in response to bradykinin stimulation, indicating that insulin potentiates Gq protein-coupled receptor signaling through an mTOR-dependent pathway. We propose that the potentiation of GPCR signaling by insulin provides a mechanism by which insulin enhances cellular responsiveness to Gq protein-coupled receptor agonists, including GPCR-mediated autocrine and paracrine loops in cancer cells.

Topics: Angiotensin II; Blotting, Western; Bombesin; Bradykinin; Calcium Signaling; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Hydrolysis; Inositol 1,4,5-Trisphosphate; Insulin; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Microscopy, Fluorescence; Myristoylated Alanine-Rich C Kinase Substrate; Neurotensin; Pancreatic Neoplasms; Phosphatidylinositol 4,5-Diphosphate; Phosphorylation; Protein Kinases; Receptors, G-Protein-Coupled; Sirolimus; TOR Serine-Threonine Kinases; Vasopressins

Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF-C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF-C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3-kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF-C and VEGF-A expression in B13LM cells, a lymphatic metastasis-prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF-C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF-A expression was inhibited by all four of these inhibitors. The serum starvation-induced expression of VEGF-C was inhibited by rapamycin, whereas that of VEGF-A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin-treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF-C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis.

Topics: Animals; Antibiotics, Antineoplastic; Blotting, Western; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; JNK Mitogen-Activated Protein Kinases; Lymphangiogenesis; Lymphatic Metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; p38 Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Protein Kinases; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Xenograft Model Antitumor Assays

Gemcitabine improves survival in pancreatic adenocarcinoma. A variety of drugs have been tested to potentiate gemcitabine treatment for pancreatic cancer cells. Two major immunosuppressive drugs, mycophenolate mofetil (MMF) and everolimus (RAD001) have been shown to exert an anti-tumoral effect, but their ability to sensitize human pancreatic cell lines during gemcitabine treatment remains unclear. We examined the effects of everolimus and MMF on gemcitabine-treated MiaPaCa and Panc-1 cell lines.. MiaPaCa and Panc-1 human pancreatic tumor cell lines were subjected to everolimus (0.001-1 microg/ml) or MMF (0.1-100 microg/ml) treatment in combination with gemcitabine (1-10(6) nM). Western blot analysis was performed for Panc-1 cells in the presence or absence of TGF-beta1 and different treatments: 0.1-100 muicro/ml MMF and 0.1-100 microg/ml everolimus. The antiproliferative effect of the treatment was assessed by BrdU test. The results were evaluated by two-way analysis of variance followed by post-hoc tests, and nonlinear regression analysis for dose-response rates.. As expected, standard treatment doses of gemcitabine decreased proliferation dose-dependently. Everolimus increased the actual EC(50) response to gemcitabine treatment (1-10(3) nM) to as much as 83.1 and 82.1% in MiaPaCa and Panc-1 cell lines, respectively. Likewise, concomitant administration with MMF altered the EC(50) of gemcitabine treatment in MiaPaCa cell lines to values between 76.8 and 85.2% for doses of >or=1 microg/ml. Even the minor dose of MMF (0.1 microg/ml) increased the antiproliferative effect of gemcitabine by 43.5% for MiaPaCa and 42.4% for Panc-1 cells. In addition, treatment of Panc-1 cells with MMF (0.1-100 microg/ml) dose-dependently inhibited TGF-beta1-induced collagen expression.. We found an overadditive antiproliferative effect of both MMF and everolimus in gemcitabine-treated MiaPaCa and Panc-1 cells in vitro, and an additional inhibitory effect of MMF on TGF-beta1-induced collagen type I expression. Interestingly, both the sensitizing effect of pancreatic cancer cells to gemcitabine treatment and the inhibition of collagen type I expression could be achieved by clinically feasible doses of everolimus and MMF. The use of these drugs is promising as a novel adjunct to standard chemotherapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Collagen Type I; Deoxycytidine; Drug Synergism; Everolimus; Gemcitabine; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pancreatic Neoplasms; Sirolimus

Sirolimus(SRL, Rapamune(â), rapamycin) is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Sirolimus exerts its biological activity by inhibiting the serine-threonine kinase mammalian target of rapamycin (mTOR), which regulates important cellular processes such as control of cell cycle, cell size, translation initiation and transcription. The ability of sirolimus to inhibit cancer cell proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anticancer agents. Here, we made mTOR as a controlling target, using a new immunosuppressant named sirolimus, to investigate the inhibitory effects of sirolimus on cell proliferation and the expression of mTOR, Hypoxia-inducible factor-1 alpha(HIF-1alpha) and vascular endothelial growth factor (VEGF) in human pancreatic carcinoma SW1990 cell line. Sirolimus is effective in vivo against pancreatic carcinoma and demonstrates that the effect of sirolimus on the inhibition of tumor cell proliferation is associated with the suppression of the mTOR/HIF-1alpha/vascular endothelial growth factor (VEGF) pathway. Thus, the targeting of mTOR signaling has been exploited as a novel therapy for human cancers.

Topics: Antibiotics, Antineoplastic; Carcinoma; Cell Line, Tumor; Cell Proliferation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Pancreatic Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer cells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinases; Signal Transduction; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Everolimus inhibits the growth of several tumor cell lines in vitro as well as tumor growth in a rat model. Mycophenolate mofetil (MMF) inhibits growth of a Walker sarcoma in a rat model in vivo. Herein we tested the in vitro antiproliferative capacity of everolimus and MMF on a pancreatic tumor cell line Panc-1 and on a small cell lung cancer cell line ScLc.. Cells were cultured under standardized conditions. Everolimus was added in increasing doses from 0.005 to 500 microg/mL; MMF was used from 0.05 to 5000 microg/mL. For co-incubation experiments, we combined everolimus (0.005 microg/mL and 0.05 microg/mL) with five concentrations of MMF; and MMF (0.5 microg/mL and 5 microg/mL) with five concentrations of everolimus. The antiproliferative capacity was assessed by a BrdU incorporation assay.. Everolimus and MMF inhibited BrdU incorporation into Panc-1 and ScLc in a dose-dependent fashion. A 50% inhibition was seen in Panc-1 only at 50 microg/mL everolimus, but in ScLc at 5 microg/mL everolimus. MMF was clearly more potent in Panc-1: 50% inhibition was observed at 5 microg/L. In ScLc, 40% inhibition of BrdU incorporation was seen only at 50 microg/L MMF. In co-incubation, an effective combination for both Panc-1 and ScLc was 5 microg/mL MMF with 0.005 microg/mL everolimus resulting in 50% inhibition of BrdU incorporation (P < .001).. Everolimus and MMF showed dose-dependent antiproliferative effects in tumor cell lines in vitro both alone and in combination. The combined use of everolimus and MMF showed supra-additive effects at concentrations used for therapeutic immunosuppression in patients.

Topics: Animals; Carcinoma 256, Walker; Cell Division; Cell Line, Tumor; Everolimus; Immunosuppressive Agents; Lung Neoplasms; Mycophenolic Acid; Pancreatic Neoplasms; Rats; Sirolimus

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Topics: Animals; Antineoplastic Agents; Benzamides; Carcinoma; Deoxycytidine; Disease Models, Animal; Female; Gemcitabine; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Kinetics; Mice; Mice, Nude; Pancreatic Neoplasms; Predictive Value of Tests; Sirolimus; Transplantation, Heterologous; Xenograft Model Antitumor Assays

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3'-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non-small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3'-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non-small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; HCT116 Cells; HT29 Cells; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Protein Kinase Inhibitors; Quinazolines; Sirolimus

We present immunohistochemical evidence that the mTOR/p70s6k pathway is activated in pancreatic tumors and show that the mTOR inhibitor and rapamycin analog CCI-779 potently suppresses the proliferation of pancreatic cancer cells. Consistent with a recent study, CCI-779 increased c-Jun phosphorylation (Ser63) in a dose- and time-dependent manner, and induced apoptosis in p53-defective BxPC-3 cells. In contrast to the study, however, we observed that CCI-779 concomitantly increased c-Jun protein levels and that its ability to induce apoptosis might not require the activated c-Jun. Furthermore, CCI-779 neither induced c-Jun phosphorylation in other p53-defective pancreatic cancer cells (MiaPaCa-2) nor inhibited their proliferation. c-Jun, in fact, appeared to be partly responsible for the resistance of MiaPaCa-2 cells to CCI-779. Together, these results indicate a complex role for c-Jun in cellular responses to CCI-779 and provide an important basis for investigating CCI-779 further as a potential therapeutic agent for pancreatic tumors.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Immunohistochemistry; Mutation; Pancreatic Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-jun; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Pancreatic cancer is still a malignant disease with a poor prognosis. Except for surgery, no curative treatment has been found, albeit large research efforts. Agents, such as growth factors and hormones, have been shown to stimulate cell proliferation, whereas their receptor antagonists have been less efficient to inhibit cell proliferation. The aim of this study was to examine the effect of inhibitors of the intracellular signal cascades on pancreatic cancer cell number.. A cell line was developed from a patient with pancreatic cancer and subcloned to three generations. The four cell lines were grown in serum-free medium. The effects of PD98059, LY294002, rapamycin and its analogue CCI-779 were tested in dose-response experiments. The chemotherapeutic agent gemcitabine, with or without combination of the other potential inhibitor drugs in different concentrations, was also examined. The cell number was evaluated with the XTT method.. PD98059 reduced the cell number in all the cell lines tested. At a concentration of 10(-4) M the cell number was reduced by 50-90%. LY294002 reduced the cell number by 40-50% at the same concentration. Two of four cell lines had their cell number reduced by CCI-779 by 60%, whereas the other two cell lines were reduced by 30%. Rapamycin or gemcitabine alone had no or only moderate effect on single cell lines. Different combinations of CCI-779 and gemcitabine led to reduction of the cell number by about 50% in concentrations up to 10(-7) M.. Inhibitors of the intracellular signal cascades can reduce the cell number of human pancreatic cancer cell lines. Inhibitors of the mitogen-activated protein kinase downstream signalling cascades seem to be more efficient than the other inhibitors. PD98059 and CCI-779, in combination with gemcitabine, could be worth studying in clinical conditions.

Topics: Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Division; Chromones; Culture Media, Serum-Free; Enzyme Inhibitors; Flavonoids; Humans; Morpholines; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Tumor Cells, Cultured

The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Everolimus; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; MAP Kinase Signaling System; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Ribosomal Protein S6 Kinases, 90-kDa; Sirolimus; Time Factors; Tumor Cells, Cultured

Despite current chemotherapies, pancreatic cancer remains an uncontrollable, rapidly progressive disease. Here, we tested an approach combining a recently described antiangiogenic drug, rapamycin, with standard gemcitabine cytotoxic therapy on human pancreatic tumor growth.. Tumor growth was assessed in rapamycin and gemcitabine-treated nude mice orthotopically injected with metastatic L3.6pl human pancreatic cancer cells. H&E staining was performed on tumors, along with Ki67 staining for cell proliferation and immunohistochemical terminal deoxynucleotidyl transferase-mediated nick end labeling and CD31 analysis. Rapamycin-treated tumor vessels were also directly examined in dorsal skin-fold chambers for blood flow after thrombosis induction. Cell death in human umbilical vein endothelial cells was assessed by flow cytometry after annexin-V staining.. Rapamycin therapy alone inhibited tumor growth and metastasis more than gemcitabine, with remarkable long-term tumor control when the drugs were combined. Mechanistically, H&E analysis revealed tumor vessel endothelium damage and thrombosis with rapamycin treatment. Indeed, dorsal skin-fold chamber analysis of rapamycin-treated tumors showed an increased susceptibility of tumor-specific vessels to thrombosis. Furthermore, terminal deoxynucleotidyl transferase-mediated nick end labeling/CD31 double staining of orthotopic tumors demonstrated apoptotic endothelial cells with rapamycin treatment, which also occurred with human umbilical vein endothelial cells in vitro. In contrast, gemcitabine was not antiangiogenic and, despite its known cytotoxicity, did not reduce proliferation in orthotopic tumors; nevertheless, rapamycin did reduce tumor proliferation.. Our data suggest a novel mechanism whereby rapamycin targets pancreatic tumor endothelium for destruction and thrombosis. We propose that rapamycin-based vascular targeting not only reduces tumor vascularization, it decreases the number of proliferating tumor cells to be destroyed by gemcitabine, thus introducing a new, clinically feasible strategy against pancreatic cancer.

Topics: Angiogenesis Inhibitors; Animals; Blood Flow Velocity; Cell Death; Cell Division; Deoxycytidine; Endothelium, Vascular; Gemcitabine; Humans; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Pancreatic Neoplasms; Sirolimus; Transplantation, Heterologous

The overall 5-year survival of patients with pancreatic cancer remains <5%. Novel therapeutic strategies are needed. We examined the effect of rapamycin, alone and in combination with antiangiogenesis therapy, on pancreatic cancer in vivo.. Human pancreatic cancer AsPC-1 cells were orthotopically injected into severe combined immunodeficient/beige mice to evaluate primary tumor growth and liver metastasis after treatment with rapamycin alone or in combination with anti-vascular endothelial growth factor antibody 2C3. Tumor cell proliferation was determined by bromodeoxyuridine incorporation. To detect tumor cell apoptosis, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. All statistical tests were two-sided.. Rapamycin, alone and in combination with 2C3, strongly inhibited primary and metastatic tumor growth in an orthotopic pancreatic cancer animal model. Furthermore, the combination therapy significantly improved the effect on liver metastasis compared with single treatment with either rapamycin (P = 0.0128) or 2C3 (P = 0.0099). Rapamycin alone inhibited pancreatic tumor cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant, stronger inhibition of tumor cell proliferation (P = 0.0002 versus rapamycin alone and P < 0.0001 versus 2C3 alone). The induction of apoptosis was significantly higher than in the rapamycin-treated group (P = 0.0039). Additionally, the combination therapy further improved suppression of tumor cell angiogenesis compared with rapamycin treatment (P = 0.029). Our studies propose new therapeutic strategies to inhibit both primary and metastatic tumor growth in pancreatic cancer. Considering the fact that liver metastasis is a crucial problem in advanced stages of pancreatic cancer, the combination therapy of rapamycin plus anti-vascular endothelial growth factor antibody 2C3 is a significant advantage compared with single treatment with rapamycin.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Proliferation; Disease Models, Animal; Female; Liver Neoplasms; Mice; Mice, SCID; Neovascularization, Pathologic; Pancreatic Neoplasms; Sirolimus

FRAP-p70s6K signaling regulates mitogenic responses to growth factors in eukaryotic cells. Constitutive p70s6K activation occurs in some human malignancies and may contribute to dysregulated cell growth. We examined whether inhibition of this pathway affects mitogen-induced proliferation and cell cycle progression of human pancreatic cancer cells in vitro.. Quiescent BxPC3 and Panc-1 human pancreatic cancer cells treated with or without 20 ng/mL rapamycin (FRAP inhibitor) were repleted with 10% FCS to induce cell cycle entry. Proliferation was measured with MTT assay. Cell cycle and apoptosis were determined by FACS analysis. Phosphorylation of p70s6K, Akt, and cdc2 was evaluated by Western blot. Statistical analysis was by two-tailed t test (P < 0.05).. Rapamycin (Rapa) inhibited the phosphorylation of p70s6K while inducing G(1) cell cycle arrest (P < 0.005). In both cell lines, Rapa inhibited serum-induced proliferation (P < 0.05) without affecting apoptosis. Cdc2 phosphorylation was inhibited by 15 min with Rapa (not shown), consistent with cell cycle arrest. Akt phosphorylation was not affected, indicating FRAP specificity of Rapa.. FRAP-p70s6K signaling appears to be necessary for G(1)-to-S phase progression and proliferation in pancreatic cancer cells. This supports earlier work demonstrating a similar regulatory role for PI-3' kinase, an upstream activator of FRAP-p70s6K.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Carrier Proteins; CDC2 Protein Kinase; Cell Division; Fetal Proteins; Flow Cytometry; G1 Phase; Humans; Immunophilins; Mitogens; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; S Phase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

The FRAP-p70s6K signaling pathway was found to be constitutively phosphorylated/active in MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a pancreatic cancer tissue sample as judged by the retarded electrophoretic mobility of the two major FRAP downstream targets, p70s6K and 4E-BP1. Treatment of cells with rapamycin, a selective FRAP Inhibitor, inhibited basal p70s6K kinase activity and induced dephosphorylation of p70s6K and 4E-BP1. Moreover, rapamycin inhibited DNA synthesis as well as anchorage-dependent and -independent proliferation in MiaPaCa-2 and Panc-1 cells. Finally, rapamycin strikingly inhibited cyclin D1 expression in pancreatic cancer cells. Thus, inhibitors of the constitutively active FRAP-p70s6K pathway may provide a novel therapeutic approach for pancreatic cancer.

Topics: Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma; Cell Cycle; Cell Cycle Proteins; Culture Media, Serum-Free; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p27; Humans; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinase 1; Neoplasm Proteins; Pancreatic Neoplasms; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Tumor Suppressor Proteins

The gastrin/CCKB (G/CCKB) G protein-coupled receptor has been shown to mediate the proliferative effects of gastrin on normal and neoplastic gastro-intestinal tissues. In the present study, we examined the signal transduction mechanisms coupled to this receptor. We report here that phosphorylation and activity of the p70S6K, whose major substrate is the ribosomal S6 protein, are enhanced in response to gastrin. These effects were completely reversed by a commonly used PI-3-kinase inhibitor, wortmannin, suggesting that p70S6K may be a downstream target of PI-3-kinase in a signaling cascade induced by gastrin. In addition, blocking PI-3-kinase activity by wortmannin partially decreased gastrin-induced MAPK activation (42% +/- 3) as well as the tyrosine phosphorylation of She (50% +/- 6), an upstream regulator of the Ras-dependent MAPK pathway. These results indicate that at least two signaling pathways lead to MAPK activation by gastrin, only one of which is sensitive to PI-3-kinase inhibitors.

Topics: Androstadienes; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Activation; Gastrins; GTP-Binding Proteins; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Polyenes; Protein Serine-Threonine Kinases; Rats; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Ribosomal Protein S6 Kinases; Ribosomal Proteins; Sirolimus; src Homology Domains; Tumor Cells, Cultured; Wortmannin