sirolimus and Neuroendocrine-Tumors

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

Both the soft tissue sarcomas and the neuroendocrine tumors are rare diseases. Therefore the recruiting of these patients was more difficult than other cancer species, and the development of the new therapy for these diseases did not readily advance. However, the identification of driver molecules for each sub-type enabled us to the development of the molecular targeted drugs. As for the GIST, several TKIs are used, but in late years it is found that susceptibility of TKIs varies according to difference in second mutation. In this chapter, the molecular target drug for the soft tissue sarcoma and the neuroendocrine tumor is reviewed.

Topics: Antibodies, Monoclonal, Humanized; Benzamides; Denosumab; Drug Discovery; Everolimus; Gastrointestinal Neoplasms; Humans; Imatinib Mesylate; Indazoles; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Niacinamide; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Sarcoma; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

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

Thoracic Neuroendocrine Tumors (TNETs) range from the more indolent behavior of the well-differentiated to the highly aggressive poorly differentiated forms. A clinical approach totally different in terms of diagnosis and treatment is therefore required. Chemotherapy and radiotherapy are the treatments of choice in poorly differentiated, whereas biological and target therapy, peptide receptor radionuclide therapy (PPRT) and temozolomide have shown efficacy in small series or in the subgroup analysis of larger trials in well differentiated. However, no specific trials have been performed before this year. The first large, prospective, randomized trial (LUNA trial) entirely dedicated to TNET is ongoing at the time of this publication.

Topics: Adrenocorticotropic Hormone; Antineoplastic Agents; Dacarbazine; Everolimus; Humans; Neuroendocrine Tumors; Sirolimus; Temozolomide; Thoracic Neoplasms

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

Neuroendocrine tumors (NETs) are a group of tumors originating in various locations, including the gastrointestinal tract, lung, and pancreas. Clinical trial design and disease management of these tumors pose a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase II and III trials demonstrates that rigorous investigation of novel agents can lead to practice-changing outcomes. Furthermore, the molecular and genetic understanding of NETs has dramatically improved during the last few years; as a result, investigators have shifted clinical trial design to focus on targeted therapies. Most of these trials have targeted the somatostatin, vascular endothelial growth factor, and mammalian target of rapamycin pathways. This review will discuss the NET treatment landscape and trials of targeted agents currently offered.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cell Differentiation; Chemoradiotherapy; Clinical Trials as Topic; Drugs, Investigational; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Neoplasm Proteins; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Radioisotopes; Sirolimus; Somatostatin; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

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

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies. Therapeutic options depend on location of the primitive tumor, its expandability, its hormonal symptoms and its differentiation. Though relatively rare, with an increasing incidence and a high prevalence digestive neuroendocrine tumors (DNETs) are ranked just behind colorectal cancer as the most common digestive cancers in developed countries. Three main therapeutic axes have been individualized in the field of well-differentiated DNETs (corresponding to grades 1 and 2 of new WHO classification 2010), firstly, antitumor activity of somatostatin analogs, particularly in slowly progressive metastatic DNETs with limited hepatic invasion, secondly, targeting angiogenesis in these hypervascular tumors and thirdly targeting the mTOR pathway involved in DNETs carcinogenesis. As a consequence of two major randomized phase III trials in 2011, sunitinib and everolimus have been considered as new therapeutic options for well-differentiated, advanced and progressive pancreatic NETs. For everolimus, another phase III study, although non-significant with the chosen criteria, showed effectiveness notably against small intestine NETs. These targeted therapies are new therapeutic weapons in management of well-differentiated DNETs, but its exact role in care strategy, in comparison with other treatments (somatostatin analogs, chemo-embolization, chemotherapy...) deserves to be precise in the future.

Topics: Algorithms; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Bevacizumab; Clinical Trials as Topic; Digestive System Neoplasms; Everolimus; Humans; Immunosuppressive Agents; Indoles; Neuroendocrine Tumors; Octreotide; Pyrroles; Sirolimus; Somatostatin; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

In the past 3 years, we have witnessed the completion of four randomized phase III studies in neuroendocrine tumors and the approval of two new drugs, everolimus and sunitinib, for the treatment of patients with well-differentiated pancreatic neuroendocrine tumors. These studies demonstrate a shift from case series and single-arm studies toward prospective, randomized controlled clinical trials and evidence-based therapy in the neuroendocrine tumor field. However, the clinical development of these agents also highlights the potential challenges awaiting other new drugs in this area. Herein, we discuss the strengths and weaknesses of the most recent phase II and phase III neuroendocrine tumor studies and discuss how limitations inherent in current trial design can lead to potential pitfalls. We also discuss how trial design can be improved, with the hope of increasing the number of drugs successfully developed to treat patients with neuroendocrine tumors.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib

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

The author aims to review the established medical treatment options of neuroendocrine tumours, which have expanded greatly in recent years and present the most important aspects to be considered in planning patients' management. Medical treatment is usually considered in advanced stages of these tumours, as well as in cases of hormone overproduction. Somatostatin analogues have been known to be effective in alleviating hormone excess syndromes, especially carcinoid syndrome for the past 25 years. There is a convincing evidence that the somatostatin analogue octreotide is useful as an antitumor agent, at least in well-differentiated small intestinal neuroendocrine tumours and probably also in those of pancreatic origin. Interferons may be also used and the indications for their use may be almost the same. Optimal patient selection is mandatory for the use of cytotoxic chemotherapy. Streptozotocin- and, recently, temozolomide-based chemotherapies should be considered in progressive phases of well differentiated (G1/G2) pancreatic neuroendocrine tumours. A cisplatin-etoposide combination is the first choice for the treatment of G3 neuroendocrine carcinomas of any origin. Recently, the mammalian target of rapamycin inhibitor everolimus and the combined tyrosine kinase inhibitor sunitinib were registered for the treatment of G1/G2 pancreatic neuroendocrine tumours. The most recent drug treatment recommendations and therapeutic algorithms to improve systemic therapy in patients with neuroendocrine tumours are summarized and novel drug candidates with particular potential for future management of these tumours are outlined.. A szerző áttekinti a neuroendokrin daganatoknak az utóbbi években jelentősen kibővült gyógyszeres kezelési lehetőségeit. Tárgyalja azokat a legfontosabb szempontokat, amelyeket a gyógyszeres kezelési terv kialakításakor figyelembe kell venni. Gyógyszeres kezelést rendszerint az előrehaladott stádiumú daganatoknál, valamint a hormontúltermeléssel járó esetekben alkalmaznak. A szomatosztatinanalógokkal 25 éve kezelik a hormontúltermelő daganatos, köztük a carcinoid szindrómás betegeket. Egyre több bizonyíték van arra is, hogy a szomatosztatinanalógok daganatellenes hatással is bírnak, különösen a vékonybél-eredetű, valamint feltételezhetően a pancreaskiindulású jól differenciált (G1/G2) daganatok esetében. Csaknem azonos az indikációs területe az interferonoknak. Jól meghatározható esetekben a citosztatikus kemoterápiának változatlanul helye van ezeknek a daganatoknak a kezelésében. A G1/G2 fokozatú, progresszív pancreas neuroendokrin daganatok esetében streptozotocin- és újabban temozolomidalapú kemoterápia alkalmazható. A G3 neuroendokrin carcinomákban ciszplatin-etopozid kombináció javasolt. A közelmúltban két új célzott gyógyszert, az emlős rapamycin célpont everolimust és a kombinált tirozinkináz-gátló sunitinibet törzskönyvezték a G1/G2 pancreas neuroendokrin daganatok kezelésére. A szerző összegzi a legújabb gyógyszeres kezelési ajánlásokat és algoritmusokat. Röviden bemutatja azokat a fejlesztés alatt álló molekulákat, amelyek további reményt nyújtanak a neuroendokrin daganatok kezelésében. Orv. Hetil., 2013, 154, 1556–1564.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Chemoembolization, Therapeutic; Embolization, Therapeutic; Everolimus; Humans; Immunosuppressive Agents; Indoles; Liver Neoplasms; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Octreotide; Protein Kinase Inhibitors; Pyrroles; Signal Transduction; Sirolimus; Somatostatin; Sunitinib

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

Neuroendocrine tumors (NETs) are heterogeneous in underlying tumor biology and clinical presentations. They are generally classified according to their degree of differentiation and sites of origin. Moreover, NETs are further characterized by their secreted bioactive neuroamine. The treatment paradigm used to be surgical intervention in early disease and mostly palliative nature in the metastatic setting. With an increase in the understanding of the molecular signaling pathways involved in tumor growth, there are various emerging treatment options for patients with advanced NETs. Somatostatin analogs have both anti-tumor effects as well as symptom palliation associated with the secreted neuropeptides. Peptide-radio-receptor treatment (PRRT) using radio-labeled peptides which binds to somatostatin receptor is a useful anti-tumor treatment but limited by general availability. Sunitinib, a multi-targeted tyrosine kinase inhibitor, has recently been shown to improve the survival of pancreatic NETs patients. Similarly, the use of an mTOR inhibitor--everolimus, either alone or in combination with somatostatin analogs have demonstrated encouraging efficacy in treating advanced NETs. The success of these two agents in pancreatic NETS supports the notion that targeting angiogenesis and/or PI3K/AKT/mTOR pathway is an important strategy for making therapeutic advances in this disease. There are now many ongoing trials in exploring the role of other novel agents in treating patients with pancreatic NETs or carcinoid. The major plaguing problem in this era is the differential response to biological agents amongst NETs of different anatomical origins. Pancreatic NETs are generally more responsive to both chemotherapy and targeted agents than NETs of other sites. Thus, the development of potential predictive and prognostic biomarkers to tailor various molecular therapies to different NETs populations is a major unmet need.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrroles; Radiopharmaceuticals; Signal Transduction; Sirolimus; Somatostatin; Sunitinib; TOR Serine-Threonine Kinases

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

Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR).. The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy.. The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy.. The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Everolimus; Humans; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Low- to intermediate-grade neuroendocrine tumor (NET) constitutes a group of indolent malignancies that share the capacity for secreting hormones and neuroamines. Until recently, there were few therapeutic options for oncologic control. The PROMID study showed that octreotide long-acting repeatable formulation can delay tumor growth in midgut NETs. And, recent phase III studies showed both everolimus and sunitinib improved progression-free survival in pancreatic NETs, validating the phosphoinositide 3-kinase/Akt/mTOR pathway and angiogenesis as important targets for further advances. Ongoing and planned pivotal studies targeting these pathways in other NET subtypes may widen their therapeutic application. Development of rational combinations may further improve therapeutic outcome. These successes and our improved understanding of the underlying molecular biology are likely to lead to further important advances on the horizon.

Topics: Antineoplastic Agents; Disease-Free Survival; Drug Therapy; Everolimus; Humans; Indoles; Models, Biological; Neuroendocrine Tumors; Octreotide; Pancreas; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrroles; Signal Transduction; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

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

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

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, whose incidence and prevalence are increasing. The clinical behavior of NEN is variable, ranging from well-differentiated slow growing tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. The term carcinoid is commonly used for the more benign variants of these neoplasms. Most frequently, carcinoids have their origin in the small intestine, followed by in the lung and other sites. Some of these tumors are associated with the carcinoid syndrome. The use of somatostatin analogs has revolutionized the clinical management of patients with carcinoids. However, although symptomatic relief and stabilization of tumor growth for various periods of time are observed in many patients treated with somatostatin analogs, tumor regression is rare. Currently, there is no other powerful antiproliferative agent available for carcinoids. Mammalian target of rapamycin (mTOR), a main protein kinase in the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations of the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NEN, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of carcinoids. However, further clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting, these drugs might be most usefully applied.

Topics: Antineoplastic Agents; Carcinoid Tumor; Cell Differentiation; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Medical Oncology; Models, Biological; Neuroendocrine Tumors; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases; Treatment Outcome

mTOR inhibitors are currently used in the treatment of solid malignancies. Since their approval, several cases of pulmonary toxicity (PT) have been described. This analysis aims to report the incidence and the risk of PT in published randomized controlled trials.. PubMed and Scopus were reviewed for phase II-III randomized controlled trials with temsirolimus and everolimus. The characteristic of each study and incidence of all- and high-grades PT were collected.. A total of 2233 patients were available for meta-analysis: 989 had breast cancer, 833 had neuroendocrine tumor and 411 had metastatic renal cell carcinoma. In patients taking mTOR inhibitors, the incidence of all- and high-grades PT was 10.4% and 2.4%, respectively. Compared to controls, the relative risk for all- and high-grades PT was 31- and 8.8-folds, respectively. No significant heterogeneity was observed between the studies. Not any relationship was found between the incidence of lung metastases, treatment exposure and the incidence of PT.. The high grade PT is a rare event and 10% of patients may experience mild grade toxicity with a worsening of quality of life and interruption of therapy in some cases. We recommend monitoring of PT in patients treated with mTOR inhibitors.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Incidence; Kidney Neoplasms; Lung; Neoplasms; Neuroendocrine Tumors; Pneumonia; Randomized Controlled Trials as Topic; Respiratory Function Tests; Risk; 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

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

Neuroendocrine tumors (NETs) represent a relatively rare form of neoplasias for which, in advanced unresectable stages, palliative treatment options remain limited largely to the use of somatostatin analogues or chemotherapy. Several newer targeted therapeutic options, alone or in combination with somatostatin analogues, are currently undergoing clinical evaluation for the treatment of NETs. This article reports the compassionate use of everolimus in combination with long-acting octreotide, in a 58-year old Italian female patient with a well-differentiated neuroendocrine gastric tumor who, since October 2004, has failed multiple previous therapies. Starting in October 2008, the patient has received intramuscular octreotide LAR 30 mg every 28 days plus everolimus 10 mg/day. The patient has reported benefits of symptoms (reduction of pain severity), objective response [improvement of liver function (reductions in LDH, ALP and total bilirubin) and chromogranin A], and radiological response (reduction in target lesions on CT). The patient has experienced an improved quality of life, increased life expectancy, and remains on this well-tolerated treatment regimen.

Topics: Antineoplastic Agents; Compassionate Use Trials; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Middle Aged; Neuroendocrine Tumors; Octreotide; Sirolimus; Stomach Neoplasms

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

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Drug Delivery Systems; Everolimus; Humans; Indoles; Neuroendocrine Tumors; Octreotide; 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

There has been a major progress in the understanding of tumor biology during the past decades and, as a consequence, new potential targets for medical treatment of cancer have been identified. Some of the new so-called targeted therapies may prove to be of value also in neuroendocrine tumors (NETs). This review focuses on recent progress in the treatment of NETs, discussing new agents and also optimization/improvement of currently available therapies.. New molecular-targeted therapies, exploiting some of the well known biological properties of NETs, such as presence of somatostatin, peptide and tyrosine kinase receptors and high vascularity, are currently being evaluated in clinical trials. Recent phase II and III data indicate that the multitarget tyrosine kinase inhibitor sunitinib has antiproliferative effects in NETs. Similarly, the mammalian target of rapamycin inhibitor everolimus has demonstrated antitumor activity in both carcinoids and pancreatic endocrine tumors. In addition, two oral chemotherapeutic agents, temozolomide and capecitabine, show promising effects and may replace streptozotocin-based regimens. The use of angiogenesis inhibitors has its rationale and bevacizumab has been tested in combination with other drugs. Radiolabeled somatostatin analogues are established as a well tolerated, effective treatment but timing is still unclear and long-term side effects need to be assessed.. Recent phase II studies have provided very promising new treatment options for NET patients. Phase III trials are needed to confirm the results and combinations of different treatment modalities are needed to make optimal use of the new modalities. Ideally, predictors of response should be developed and the new definitions of response necessitates careful monitoring with biomarkers and imaging procedures including functional imaging. Whether the new therapies prolong survival of the patients should also be established.

Topics: Antineoplastic Agents; Capecitabine; Dacarbazine; Deoxycytidine; Drug Therapy; Everolimus; Fluorouracil; Humans; Indoles; Neuroendocrine Tumors; Octreotide; Pyrroles; Sirolimus; Sunitinib; Temozolomide; Treatment Outcome

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for "REnal Cell cancer treatment with Oral RAD001 given Daily"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Therapy, Combination; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Practice Guidelines as Topic; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

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

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

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

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

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

Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET.. Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity.. One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand-foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients.. Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Everolimus; Feasibility Studies; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neuroendocrine Tumors; Niacinamide; Phenylurea Compounds; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor A

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

The incidence of neuroendocrine tumors (NETs) has increased approximately fivefold since the 1980s. A similar increase in the incidence of lung NETs has been reported, but therapy has not been optimized.. This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide long-acting repeatable (LAR) in a cohort of patients with low- to intermediate-grade advanced lung NET from the phase 3, randomized, placebo-controlled RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors) study. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes.. Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P 5 .228). More patients receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST [Response Evaluation Criteria in Solid Tumors]) than those receiving placebo plus octreotide LAR (27%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus.. This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population.. ClinicalTrials.gov; No.: NCT00412061

Topics: Aged; Antineoplastic Agents; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Lung Neoplasms; Male; Neoplasm Grading; Neuroendocrine Tumors; Octreotide; Sirolimus; Survival Rate; Treatment Outcome

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.. Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4-month progression-free survival rate (PFSR). The hypothesis of the current study was that the 4-month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).. A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4-month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty-eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%-18.6%) and 93.9% (95% CI, 85.8%-100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months-26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months-23.0 months) and the 4-month PFSR was 90.0%. Twenty-one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months-7.0 months) and the 4-month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).. Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Paraganglioma; Pheochromocytoma; Prognosis; Sirolimus; Survival Rate

Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. Pasireotide is a somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate the safety and feasibility of combining pasireotide with everolimus in patients with advanced neuroendocrine tumors. Cohorts of patients with advanced neuroendocrine tumors were treated with escalating doses of pasireotide (600-1200  μg s.c. b.i.d., followed by pasireotide LAR 40-60  mg i.m. monthly) and everolimus (5-10  mg daily). Twenty-one patients were treated. Dose-limiting toxicities consisting of grade 3 rash and grade 3 diarrhea were observed. Twelve patients were safely treated at the maximum protocol-defined dose level of pasireotide LAR 60  mg i.m. monthly and everolimus 10  mg daily. Hyperglycemia was common; other observed toxicities were consistent with the known toxicities of either agent alone. Partial tumor response was observed in one patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60  mg i.m. monthly in combination with everolimus 10  mg daily is feasible and associated with preliminary evidence of antitumor activity in patients with advanced neuroendocrine tumors. Further studies evaluating this combination are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuroendocrine Tumors; Sirolimus; Somatostatin

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

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

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

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

Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neuroendocrine Tumors; Sirolimus; Small Cell Lung Carcinoma; Tumor Suppressor Protein p53

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

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

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

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

Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients.. Patients with advanced progressive well-differentiated NETs underwent (89)Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. (89)Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly).. In 4 of the 14 patients entered, no tumor lesions were visualized with (89)Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of -7% at 2 wk (P = 0.09) and a median of -35% at 12 wk (P < 0.001). The difference in SUVmax at 2 and 12 wk with respect to SUVmax at baseline correlated with percentage change on CT at 6 mo (r(2) = 0.51, P < 0.05, and r(2) = 0.61, P < 0.01, respectively).. This study demonstrates variable (89)Zr-bevacizumab PET tumor uptake in NET patients. (89)Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial (89)Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGF-directed treatment in NET patients.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Bevacizumab; Biological Transport; Chromogranin A; Everolimus; Feasibility Studies; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Positron-Emission Tomography; Radioisotopes; Sirolimus; Treatment Outcome; Vascular Endothelial Growth Factor A; Zirconium

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

Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.

Topics: Acetamides; Antineoplastic Agents; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Humans; Neuroendocrine Tumors; Nuclear Proteins; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; RNA-Binding Proteins; Sirolimus; Transcription Factors

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

Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice. Previous results showed that diet restriction (DR) had minimal or no effect on the lifespan of Rb1+/- mice, suggesting that the beneficial response to DR is dependent on pRb1. Since long-term eRapa treatment may at least partially mimic chronic DR in lifespan extension, we predicted that it would have a minimal effect in Rb1+/- mice. Beginning at 9 weeks of age until death, we fed Rb1+/- mice a diet without or with eRapa at 14 mg/kg food, which results in an approximate dose of 2.24 mg/kg body weight per day, and yielded rapamycin blood levels of about 4 ng/ml. Surprisingly, we found that eRapa dramatically extended life span of both female and male Rb1+/- mice, and slowed the appearance and growth of pituitary and decreased the incidence of thyroid tumors commonly observed in these mice. In this model, eRapa appears to act differently than DR, suggesting diverse mechanisms of action on survival and anti-tumor effects. In particular the beneficial effects of rapamycin did not depend on the dose of Rb1.

Topics: Animals; Diet; Female; Longevity; Male; Mice; Neuroendocrine Tumors; Retinoblastoma Protein; Sirolimus

Topics: Antineoplastic Agents; Everolimus; Female; Humans; Immunosuppressive Agents; Lung Neoplasms; Male; Neuroendocrine Tumors; Octreotide; Sirolimus

The mammalian target of rapamycin inhibitors are normally favored as immunosuppressant agents for solid organ transplantation such as kidney, liver or heart. Only in recent years have they been increasingly administered for the treatment of neuroendocrine tumors. Even though mammalian target of rapamycin inhibitors are known to exhibit specific side effects, everolimus-related severe hepatic steatosis has not as yet been described in the literature. We report the case of a 76-year-old man who developed severe hepatic steatosis within four weeks of treatment with everolimus as concomitant tumor therapy for a progressively growing neuroendocrine carcinoma of the ileum. A diagnosis of hepatic steatosis was established using computer tomography and fibroscan©. Other underlying causes for steatosis hepatis could be excluded. Further studies are warranted to explain the underlying mechanisms.

Topics: Aged; Everolimus; Fatty Liver; Humans; Immunosuppressive Agents; Liver Neoplasms; Male; Neuroendocrine Tumors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

Gastric neuroendocrine tumors (NET) are rare and are classified into 3 types: type 1 and 2 (characterized by hypergastrinemia), and type 3 (characterized by normal gastrin). Surgery is the standard procedure, and systemic treatment is reserved for unresectable disease. Currently, targeted therapies are being evaluated in NET. The activity of everolimus, an mTOR inhibitor, has been shown in pancreatic NET but not reported in type 3 gastric carcinoid tumors.. Here we report a case of a patient who, after multiple lines of systemic therapy, had a prolonged disease control of nearly 1 year, significant clinical benefit, and minor tumor shrinkage with oral everolimus 10 mg continuously.. There is no effective treatment for type 3 gastric carcinoid tumors. The frequency of mTOR expression in these tumors is not known, but the case reported here suggests that inhibition of this pathway may play an important role.

Topics: Antineoplastic Agents; Everolimus; Humans; Male; Middle Aged; Neuroendocrine Tumors; Sirolimus; Stomach Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

Neuroendocrine (NE) phenotypes characterize a spectrum of lung tumors, including low-grade typical and intermediate-grade atypical carcinoid, high-grade large-cell NE carcinoma and small cell lung carcinoma. Currently, no effective treatments are available to cure NE lung tumors, demanding identification of biological features specific to these tumors. Here, we report that autophagy has an important role for NE lung tumor cell proliferation and survival. We found that the expression levels of the autophagy marker LC3 are relatively high in a panel of lung tumor cell lines expressing high levels of neuron-specific enolase (NSE), a key NE marker in lung tumors. In response to bafilomycin A1 and chloroquine, NE lung tumor cells exhibited cytotoxicity whereas non-NE lung tumor cells exhibited cytostasis, indicating a distinct role of autophagy for NE lung tumor cell survival. Intriguingly, in certain NE lung tumor cell lines, the levels of processed LC3 (LC3-II) were inversely correlated with AKT activity. When AKT activity was inhibited using AKTi or MK2206, the levels of LC3-II and SQSTM1/p62 were increased. In contrast, torin 1, rapamycin or mTOR knockdown increased p62 levels, suggesting that these two pathways have opposing effects on autophagy in certain NE lung tumors. Moreover, inhibition of one pathway resulted in reduced activity of the other, suggesting that these two pathways crosstalk in the tumors. These results suggest that NE lung tumor cells share a common feature of autophagy and are more sensitive to autophagy inhibition than non-NE lung tumor cells.

Topics: Adaptor Proteins, Signal Transducing; Antimalarials; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chloroquine; Enzyme Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Lung Neoplasms; Macrolides; Microtubule-Associated Proteins; Naphthyridines; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Phosphorylation; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Sequestosome-1 Protein; Signal Transduction; Sirolimus; Small Cell Lung Carcinoma; TOR Serine-Threonine Kinases

Novel therapeutic agents are currently being investigated for neuroendocrine tumour treatment.. We report here on the case of a patient presenting with hypersensitivity pneumonitis while being treated with everolimus, a mammalian target of rapamycin (mTOR) inhibitor.. Side effects of everolimus should be familiar to clinicians, including nonspecialists, and be monitored carefully to allow for prompt management.

Topics: Alveolitis, Extrinsic Allergic; Antineoplastic Agents; Everolimus; Humans; Intestine, Small; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Sirolimus

Chromogranin A is a neuroendocrine secretory product and its loss is a feature of malignant NEN de-differentiation. We hypothesized that chromogranin A fragments were differentially expressed during NEN metastasis and played a role in the regulation of NEN proliferation.. Chromogranin A mRNA (PCR) and protein (ELISA/western blot) were studied in 10 normal human mucosa, 5 enterochromaffin cell preparations, 26 small intestinal NEN primaries and 9 liver metastases. Cell viability (WST-1 assay), proliferation (bromodeoxyuridine ELISA) and expression of AKT/AKT-P (CASE ELISA/western blot) in response to chromogranin A silencing, inhibition of prohormone convertase and mTOR inhibition (RAD001/AKT antisense) as well as different chromogranin A fragments were examined in 4 SI-NEN cell lines.. Chromogranin A mRNA and protein levels were increased (37-340 fold, p<0.0001) in small intestinal NENs compared to normal enterochromaffin cells. Western blot identified chromogranin A-associated processing bands including vasostatin in small intestinal NENs as well as up-regulated expression of prohormone convertase in metastases. Proliferation in small intestinal NEN cell lines was decreased by silencing chromogranin A as well as by inhibition of prohormone convertase (p<0.05). This inhibition also decreased secretion of chromogranin A (p<0.05) and 5-HT (p<0.05) as well as expression of vasostatin. Metastatic small intestinal NEN cell lines were stimulated (50-80%, p<0.05) and AKT phosphorylated (Ser473: p<0.05) by vasostatin I, which was completely reversed by RAD001 (p<0.01) and AKT antisense (p<0.05) while chromostatin inhibited proliferation (~50%, p<0.05).. Chromogranin A was differentially regulated in primary and metastatic small intestinal NENs and cell lines. Chromogranin A fragments regulated metastatic small intestinal NEN proliferation via the AKT pathway indicating that CgA plays a far more complex role in the biology of these tumors than previously considered.

Topics: Calreticulin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromogranin A; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Liver Neoplasms; Neuroendocrine Tumors; Peptide Fragments; Phosphorylation; Proprotein Convertases; Proto-Oncogene Proteins c-akt; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Aged; Antineoplastic Agents; Contraindications; Dose-Response Relationship, Drug; Everolimus; Female; Humans; Kidney Failure, Chronic; Liver Neoplasms; Neuroendocrine Tumors; Renal Dialysis; Sirolimus; Treatment Outcome

The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade.. A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed.. Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events.. Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Sirolimus

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

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

Mammalian target of rapamycin (mTOR) inhibitors have been clinically used as anticancer agents in several types of human malignancies including neuroendocrine tumor (NET) but the development of clinical resistances or their therapeutic limitations have been also reported. This clinical resistance has been proposed to be partly due to a compensatory activation of an mTOR upstream factor Akt and MEK/ERK pathway in NET cells but its details have not necessarily been reported. Therefore, in this study, we examined the effects of mTOR inhibitors on these activations and of the concomitant treatment of mTOR and MEK inhibitors in two NET cell lines, NCI-H727 and COLO320. We evaluated the effects of RAD001, mTOR inhibitor, and U0126, MEK inhibitor, on cell proliferation and migration of these cells. In addition, an alteration of the factors involved in Akt/mTOR and MEK/ERK pathways was also examined under administration of these agents. RAD001 and U0126 treatment significantly inhibited cell proliferation and their combined treatment synergistically decreased it in both cell lines. Additionally, these treatments above decreased the expression of cell cycle-related factors, suggestive of an involvement of cell cycle arrest in therapeutic effects. The combined treatment also inhibited the cell migration in NCI-H727 via the decrement of MMP2 and 9 in an additive manner. We demonstrated the potential synergistic/combined effects of inhibitors of mTOR and MEK on cell proliferation and migration. These results suggest the potential therapeutic efficacy of the combined therapy of mTOR and MEK inhibitors or a dual inhibitor for the treatment of NET patients.

Topics: Antineoplastic Agents; Butadienes; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromogranin A; Drug Synergism; Everolimus; Gene Expression; Humans; MAP Kinase Kinase Kinases; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neuroendocrine Tumors; Nitriles; Phosphopyruvate Hydratase; Protein Kinase Inhibitors; Sirolimus; Synaptophysin; TOR Serine-Threonine Kinases; Vesicular Transport Proteins

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

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

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

The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

Topics: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Enzyme Inhibitors; Everolimus; Humans; Imidazoles; Neuroendocrine Tumors; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-bcl-2; Pyridines; Quinolines; Receptor, IGF Type 1; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; TNF-Related Apoptosis-Inducing Ligand; 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

Treatment of small intestinal neuroendocrine tumors (SINETs) with mammalian target of rapamycin (mTOR) inhibitors alone or with somatostatin analogs has been proposed as effective therapy, because both agents have been reported to exhibit antiproliferative activity. Because adenocarcinomas escape mTOR inhibition, we examined whether the escape phenomenon occurred in SINETs and whether usage of somatostatin analogs with mTOR inhibitors surmounted loss of inhibition.. The effects of the somatostatin analog octreotide (OCT), the mTOR inhibitor RAD001 (RAD), or the combination were evaluated in SINET cell lines (KRJ-I, H-STS) using cell viability assays, western blotting, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction to assess antiproliferative signaling pathways and feedback regulation.. RAD (10(-9) M) incompletely decreased cell viability (-40% to +15%); growth escape (P < .001) was noted at 72 hours in both cell lines. Phosphorylated (p)mTOR/mTOR and pp70S6K/p70S6K ratios were decreased but were associated with increases in phosphorylated extracellular signal-regulated kinase (pERK)/ERK and pAKT/AKT in both cell lines, whereas phosphorylated insulin-like growth factor 1 receptor (pIGF-1R)/IGF-1R levels were elevated only in H-STS cells. Increased (P < .05) transcript levels for AKT1, MAPK, mTOR, IGF-1R, IGF-1, and TGFβ1 were evident. OCT (10(-6) M) itself had no significant effect on growth signaling in either cell line. An antiproliferative effect (66 ± 5%) using OCT+RAD was only noted in the KRJ-I cells (P < .05).. SINET treatment with the mTOR inhibitor RAD had no antiproliferative effect based on activation of pAKT and pERK1/2. A combinatorial approach using OCT and RAD failed to overcome this escape phenomenon. However, differences in RAD response rates in individual NET cell lines suggested that pretreatment identification of different tumor sensitivity to mTOR inhibitors could provide the basis for individualized treatment.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Everolimus; Humans; Intestinal Neoplasms; Intestine, Small; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuroendocrine Tumors; Octreotide; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.

Topics: Adolescent; Adult; Aged; Animals; Cell Line, Tumor; Everolimus; Female; Humans; Male; Mice; Middle Aged; Molecular Targeted Therapy; Neuroendocrine Tumors; Prognosis; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

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

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

Metastatic gastrointestinal neuroendocrine tumors (NETs) frequently are refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets.. Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An in vitro, sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic short interfering RNA administration targeted Src.. By using the Aldefluor assay, aldehyde dehydrogenase-positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± standard error of the mean) of cells from 19 patient samples. Although many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH- cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH- cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH- or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%.. CSCs are present in NETs, as shown by in vitro sphere formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.

Topics: Aldehyde Dehydrogenase; Carcinogenicity Tests; Carcinoid Tumor; Cell Line, Tumor; Cells, Cultured; CSK Tyrosine-Protein Kinase; Gastrointestinal Neoplasms; Humans; In Vitro Techniques; Neoplastic Stem Cells; Neuroendocrine Tumors; Protein-Tyrosine Kinases; Signal Transduction; Sirolimus; src-Family 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: Antibodies, Monoclonal; Antineoplastic Agents; Cell Differentiation; Combined Modality Therapy; Disease Management; Enzyme Inhibitors; Everolimus; Humans; Neuroendocrine Tumors; Sirolimus

Several studies have established a link between aberrant PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling and neuroendocrine tumor disease. In this study, we comparatively investigate the antitumor potential of novel small-molecule inhibitors targeting mTOR (RAD001), mTOR/PI(3)K (NVP-BEZ235) and Raf (Raf265) on human NET cell lines of heterogeneous origin. All inhibitors induced potent antitumor effects which involved the induction of apoptosis and G0/G1 arrest. However, the dual mTOR/PI(3)K inhibitor NVP-BEZ235 was more efficient compared to the single mTOR inhibitor RAD001. Consistently, NVP-BEZ235 prevented the negative feedback activation of Akt as observed after treatment with RAD001. Raf265 inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion, suggesting the existence of a compensatory feedback loop on PI3K-Akt signaling. Finally, combined treatment with RAD001 or NVP-BEZ235 and Raf265 was more efficient than single treatment with either kinase inhibitor. Together, our data provide a rationale for dual targeting of PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling in NET disease.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Everolimus; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; G1 Phase; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Neuroendocrine Tumors; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Quinolines; raf Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as somatostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1alpha under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chromones; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Insulin; Insulin Secretion; Intracellular Signaling Peptides and Proteins; MAP Kinase Kinase 1; Mice; Morpholines; Neuroendocrine Tumors; Octreotide; p38 Mitogen-Activated Protein Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Rats; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

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

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

Topics: Adult; Aged; Analysis of Variance; Blotting, Western; Cell Line, Tumor; Cell Survival; Cells, Cultured; Female; Humans; Immunohistochemistry; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neuroendocrine Tumors; Phosphorylation; Prognosis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Drug Monitoring; Humans; Neuroendocrine Tumors; Octreotide; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The mode of action of the somatostatin analog octreotide on neuro-endocrine tumour proliferation is largely unknown. Overexpression of the proto-oncogene Akt/PKB (protein kinase B) has been demonstrated in certain neuro-endocrine tumours: Akt activates downstream proteins including mTOR and p70S6K, which play an important role in cell proliferation. RAD001 (everolimus) is a novel agent that is being trialled in the treatment of neuro-endocrine tumours, and is known to interact with mTOR. We explored the mechanism of action of octreotide, RAD001, and their combination on cell proliferation and kinase activation in a neuro-endocrine tumour cell line (rat insulinoma cell line, INS1).. Proliferation assays were used to determine the effects of octreotide, RAD001, and their combination on cell proliferation. Western blotting was used to characterize the expression of phosphorylated Akt, phosphorylated TSC2, phosphorylated mTOR, and phosphorylated 70S6K.. Treatment with octreotide and RAD001 inhibited proliferation and attenuated phosphorylation of all downstream targets of Akt: TSC2, mTOR, and p70S6K.. In this cell model, octreotide and RAD001 appear to act through a similar pathway and inhibit the Akt-mTOR-p70S6 kinase pathway downstream of Akt. There may be some overlapping effects of the two inhibitors on the mTOR pathway, although it is likely that other additional effects may differentiate the two agents.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Everolimus; Neuroendocrine Tumors; Octreotide; Protein Kinases; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

The mammalian target of rapamycin (mTOR) signaling pathway has emerged as a promising target for cancer therapy. Rapamycin inhibits mTOR activity but induces upstream signaling, leading to Akt activation, potentially limiting antitumor activity. Octreotide, a somatostatin analog, decreases phosphatidylinositol-3-kinase/Akt signaling in some models, and thus theoretically may enhance rapamycin's antitumor activity. The aim of this study was to determine the antitumor activity of rapamycin and octreotide as single agents and in combination in neuroendocrine tumors. In carcinoid cell lines BON-1 and NCI-H727, cell proliferation was significantly inhibited by rapamycin in vitro, although rapamycin treatment did lead to Akt phosphorylation. Octreotide had limited antiproliferative effects alone, and did not demonstrate synergistic or additive interactions with rapamycin. Furthermore, octreotide did not overcome rapamycin-induced Akt phosphorylation. In vivo, rapamycin alone caused significant tumor suppression. Octreotide alone did not inhibit in vivo tumor growth and did not enhance rapamycin-mediated growth inhibition. In conclusion, rapamycin causes significant growth inhibition in carcinoid tumor cell lines in vitro and in vivo, thus mTOR is a promising therapeutic target for neuroendocrine tumors. Octreotide does not enhance the efficacy of rapamycin's antiproliferative effects in the models tested, and does not inhibit rapamycin-mediated feedback activation of Akt. Further study is needed in order to determine whether octreotide or other somatostatin analogs enhance the efficacy of mTOR inhibitors in other models.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Carcinoid Tumor; Cell Proliferation; Cells, Cultured; Humans; Male; Mice; Mice, Inbred BALB C; Neuroendocrine Tumors; Octreotide; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinases; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Disease Progression; Humans; Neuroendocrine Tumors; Sirolimus; Treatment Outcome