pasireotide and Neuroendocrine-Tumors

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.

Topics: Adenoma; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Hormones; Humans; Middle Aged; Neuroendocrine Tumors; Pituitary Neoplasms; Prolactin; Prolactinoma; Somatostatin

Insulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterized by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2 cm), well-demarcated, solitary nodule that can arise in any part of the organ. Treatment for sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues is commonly used first line for symptom control, albeit with variable efficacy. Other medical options are emerging, including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multisomatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its antitumour/antiproliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease, while cytotoxic chemotherapy can be used in patients with higher-grade tumours. This review considers the developments in the medical and other nonsurgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails.

Topics: Animals; Everolimus; Humans; Hypoglycemia; Insulinoma; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible.. Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed.. Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.

Topics: Acromegaly; Animals; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pituitary ACTH Hypersecretion; Somatostatin

Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affinity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affinity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Somatostatin

Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs. Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs. Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.

Topics: Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Receptors, Somatostatin; Somatostatin

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Pyrroles; Somatostatin; Sunitinib; Syndrome; Treatment Outcome

Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.

Topics: Acromegaly; Adenoma; Antineoplastic Agents; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms

Somatostatin analogs (SSAs) were initially developed as antisecretory agents used for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating evidence has also supported their role as antiproliferative agents in well or moderately differentiated NETs. The phase III PROMID trial demonstrated that octreotide long-acting repeatable (LAR) can significantly prolong time to progression among patients with metastatic midgut NETs. More recently, the randomized CLARINET trial reported a significant improvement in progression-free survival in a heterogeneous population of patients with gastroenteropancreatic (GEP)-NETs treated with depot lanreotide. Octreotide and lanreotide target somatostatin receptor subtypes in a similar fashion, and appear to be clinically interchangeable; however, comparative noninferiority trials have not been performed. Further studies are needed to evaluate the efficacy of novel SSAs such as pasireotide in the refractory setting, and the role of high-dose SSAs for symptom and tumor control.

Topics: Antineoplastic Agents, Hormonal; Disease-Free Survival; Humans; Intestinal Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms

Carcinoid crisis is a life-threatening syndrome of neuroendocrine tumors (NETs) characterized by dramatic blood pressure fluctuation, arrhythmias, and bronchospasm. In the era of booming anti-tumor therapeutics, this has become more important since associated stresses can trigger carcinoid crisis. Somatostatin analogues (SSTA) have been recommended for prophylactic administration before intervention procedures for functioning NETs. However, the efficacy is still controversial. The aim of this article is to review efficacy of SSTA for preventing carcinoid crisis.. PubMed, Cochrane Controlled trials Register, and EMBASE were searched using 'carcinoid crisis' as a search term combining terms with 'somatostatin'; 'octreotide'; 'lanreotide' and 'pasireotide' until December 2013.. Twenty-eight articles were retrieved with a total of fifty-three unique patients identified for carcinoid crisis. The most common primary sites of NETs were the small intestine and respiratory tract. The triggering factors for carcinoid crisis included anesthesia/ surgery (63.5%), interventional therapy (11.5%), radionuclide therapy (9.6%), examination (7.7%), medication (3.8%), biopsy (2%) and spontaneous (2%). No randomized controlled trials (RCTs) were identified and two case-control studies were included to assess the efficacy of SSTA for preventing carcinoid crisis by meta-analysis. The overall pooled risk of perioperative carcinoid crisis was similar despite the prophylactic administration of SSTA (OR 0.44, 95% CI: 0.14 to 1.35, p=0.15).. SSTA was not helpful for preventing carcinoid crisis based on a meta-analysis of retrospective studies. Attentive monitoring and careful intervention are essential. Future studies with better quality are needed to clarify any effect of SSTA for preventing carcinoid crisis.

Topics: Humans; Intestine, Small; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Respiratory System; Somatostatin

Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst2. Pasireotide is a sst multireceptor ligand with affinity for sst1, sst2, sst3 and sst5 and this broader binding profile may translate into a higher efficacy with respect to suppression of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushing's disease and neuroendocrine tumors.

Topics: Acromegaly; Humans; Ligands; Neuroendocrine Tumors; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

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

Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.

Topics: Antineoplastic Agents; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Peptides, Cyclic; Receptors, Somatostatin; Somatostatin; Treatment Outcome

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

Neuroendocrine tumors (NETs) are relatively rare neoplasms that often present as diagnostic dilemmas due to obscure or non-specific symptoms. The ability of carcinoid tumors to cause clinical symptoms by secretion of hormones or biogenic amines is best recognised in the form of the carcinoid syndrome. Although generally slow growing, a significant minority demonstrate aggressive tumor growth. Ten-twenty percent of pancreatic NETs may be associated with hereditary disorders such as multiple endocrine neoplasia-1 (MEN-1) and less frequently, Von Hippel Lindau, which should be considered in the investigation and management of these patients. A small percentage of NETs are associated with co-existing synchronous non-carcinoid neoplasm. The aim of this paper was to review the optimal management in patients with NETs. The therapeutic options which are reviewed, including the use of somatostatin analogues, the role of surgery, the use of chemotherapy, biotherapy using interferon, peptide receptor targeted therapy. In addition, the challenging interventional management of liver metastases is discussed, including the role of hepatic-artery embolization, radiofrequency ablation and the place of orthotoptic liver transplantation in selected patients. Authors have focused on the newest therapeutic modalities, e.g., radionuclide peptide receptor targeted therapy with Yttrium-90 and Lutetium-177, the newest somatostatin analogues such as pasireotide and angiogenic inhibitors. In conclusion, with the increasing number of investigative procedures and therapeutic options available to diagnose and treat carcinoid tumors, it is vital to have a multidisciplinary approach. Furthermore, additional scientific research and controlled clinical trials are needed to determine the efficacy of the many treatment options, which for these rare tumors can only be achieved by collaboration.

Topics: Angiogenesis Inhibitors; Biochemistry; Carcinoid Tumor; Embolization, Therapeutic; Gastrinoma; Hepatic Artery; Humans; Insulinoma; Liver Transplantation; Malignant Carcinoid Syndrome; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Patient Selection; Receptors, Peptide; Somatostatin; Vipoma; von Hippel-Lindau Disease

Neuroendocrine tumors (NETs) are relatively rare and comprise carcinoids, gastrinomas, and poorly differentiated endocrine carcinomas (PDECs). Diagnostic procedures should include endoscopy with biopsy, computed tomography, or magnetic resonance imaging. Fluorodeoxyglucose positron-emission tomography is also useful for the detection of extraabdominal metastases. Complete resection with lymph node dissection, as recommended for other cancers, such as distal gastrectomy, total gastrectomy, and pancreaticoduodenectomy, should be attempted in localized NETs. Endoscopic submucosal dissection should also be attempted in early-stage disease. Both curative and palliative surgery is indicated for patients with liver metastases of foregut-origin NETs. Combination chemotherapy (cisplatin/carboplatin + etoposide) may be useful in treating PDECs with metastases. Combination therapies with streptozotocin, doxorubicin, and 5-fluorouracil are also useful for the treatment of carcinoid tumors. Somatostatin analogues, such as octreotide and SOM 230, have been registered for the control of hormonal symptoms in patients with gastrointestinal NETs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Diagnostic Imaging; Digestive System Surgical Procedures; Duodenal Neoplasms; Esophageal Neoplasms; Humans; Lymph Node Excision; Neuroendocrine Tumors; Octreotide; Somatostatin; Stomach Neoplasms

Somatostatin is a peptide hormone that posses several biological functions of which inhibition of hormone secretion from endocrine cells is one. Neuroendocrine tumors usually express somatostatin receptors (SSTRs), although the subtypes and number of SSTRs expressed in a certain tumor is very variable. The primary goal of somatostatin analog treatment is to decrease hormone production and secretion, resulting in control of hormone induced symptoms, while the ability of somatostatin analogs to retard tumor growth is less well documented. All patients considered for somatostatin analog treatment should undergo SSTR scintigraphy (111In-pentetreotide) to establish SSTR status, since the expression is usually correlated to therapeutic response. By this approach, it is possible to select patients suitable for treatment. Among patients with functioning neuroendocrine tumors expressing SSTR, more than 80% respond with symptomatic relief during somatostatin analog treatment, while treatment of non-functioning tumors still remains somewhat controversial.

Topics: Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin; Stomach Neoplasms; Thoracic Neoplasms

More than 30 years have passed since somatostatin was discovered and its hormonal function defined. The wide range of anatomical distribution and actions of somatostatin and its receptors have stimulated intense scientific and clinical interest. The development of somatostatin analogues helped define its usefulness in the treatment of endocrine diseases and cancer. The molecular cloning of five distinct subtypes of somatostatin receptors in the 1980s has significantly increased our insight into the biology of somatostatin and its receptor subtypes and has led to the design and development of subtype-selective peptides and nonpeptide agonists and antagonists. In the future, the development of somatostatin-receptor-mediated treatment will go along different lines. Tumor-targeted radioactive treatment based on somatostatin analogues will be further developed and improved. New somatostatin analogues will come into clinical practice, both receptor subtype-specific analogues, but also pan-receptor analogues. One is currently in clinical trial--SOM230--which is a cyclo-hexapeptide binding with high affinity to receptor type 1, 2, 3 and 5, but not 4. It has already shown activity both in acromegaly and in neuroendocrine gastrointestinal tumors. Preclinical studies on somatostatin analogues, coupled to cytotoxic agents, have shown rather promising results and will hopefully be further developed in clinical trials. Another interesting area is treatment of neuroendocrine gut tumors with ultra-high doses of somatostatin analogues, which has demonstrated significant clinical effects in patients resistant to standard-dose treatment with the same somatostatin analogue.

Topics: Binding Sites; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Somatostatin; Somatostatin

Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT.. This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg/day), pasireotide (600 μg twice daily), and SIRT (SIR-Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long-acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose-limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers-angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin-like growth factor binding protein 1, insulin-like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2-were assessed. The Norfolk Quality of Life-Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL).. Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well-differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver-only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment-related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression-free survival and overall survival were 18.6 and 46.3 months, respectively.. The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. Cancer 2018;124:1992-2000. © 2018 American Cancer Society.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Chemoradiotherapy; Dose-Response Relationship, Drug; Embolization, Therapeutic; Everolimus; Female; Humans; Kaplan-Meier Estimate; Liver; Liver Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Neuroendocrine Tumors; Progression-Free Survival; Quality of Life; Response Evaluation Criteria in Solid Tumors; Somatostatin

Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET.. Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis.. Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively.. The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Everolimus; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin; Survival Analysis; Young Adult

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.

Topics: Adult; Aged; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Prospective Studies; Receptors, Somatostatin; Somatostatin

Pasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst1-3, 5). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs.. In this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months.. Forty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels).. This study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.

Topics: Blood Glucose; Chemistry, Pharmaceutical; Defecation; Delayed-Action Preparations; Diarrhea; Endpoint Determination; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Neuroendocrine Tumors; Somatostatin

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

Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diarrhea; Drug Resistance, Neoplasm; Female; Flushing; Gastrointestinal Agents; Humans; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Quality of Life; Somatostatin; Treatment Outcome

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

Topics: Adenoma; Adrenocorticotropic Hormone; Carcinoid Tumor; Cushing Syndrome; Humans; Lung Neoplasms; Neuroendocrine Tumors

Increasingly common, neuroendocrine tumors (NETs) are regarded nowadays as neoplasms potentially causing debilitating symptoms and life-threatening medical conditions. Pheochromocytoma is a NET that develops from chromaffin cells of the adrenal medulla, and is responsible for an excessive secretion of catecholamines. Consequently, patients have an increased risk for clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Somatostatin analogues are among the main anti-secretory medical drugs used in current clinical practice in patients with NETs. However, their impact on pheochromocytoma-associated catecholamine hypersecretion remains incompletely explored. This study investigated the potential efficacy of octreotide and pasireotide (SOM230) on human tumor cells directly cultured from freshly resected pheochromocytomas using an implemented catecholamine secretion measurement by carbon fiber amperometry. SOM230 treatment efficiently inhibited nicotine-induced catecholamine secretion both in bovine chromaffin cells and in human tumor cells whereas octreotide had no effect. Moreover, SOM230 specifically decreased the number of exocytic events by impairing the stimulation-evoked calcium influx as well as the nicotinic receptor-activated inward current in human pheochromocytoma cells. Altogether, our findings indicate that SOM230 acts as an inhibitor of catecholamine secretion through a mechanism involving the nicotinic receptor and might be considered as a potential anti-secretory treatment for patients with pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Catecholamines; Cell Line, Tumor; Humans; Neuroendocrine Tumors; Octreotide; Pheochromocytoma; Somatostatin

Post-operative pancreatic fistula (POPF) is a feared complication after a pancreaticoduodenectomy. Previously in a randomized trial found fewer clinically relevant fistulas (CR-POPF) accompanying administration of perioperative pasireotide. Our hospital previously found that the risk for CR-POPF reached 7% in pancreaticoduodenectomy patients. Here, we aimed to determine the CR-POPF rate accompanying prophylactic pasireotide in patients with a normal pancreas at resection level.. In this clinical study, perioperative pasireotide was administered to pancreaticoduodenectomy patients treated between 1 July 2014 and 30 April 2016. High-risk individuals were defined preoperatively by the surgeon based on the following: no dilatation of the pancreatic duct, suspected soft pancreas and a cystic or neuroendocrine tumor at the head of the pancreas. If the pancreas was considered hard at surgery, thereby carrying a lower risk for fistula, pasireotide was discontinued following one preoperative 900-μg dose. Among high-risk patients, pasireotide was continued for one week or until discharge from the hospital.. During the study period, 153/215 pancreatic operations were pancreaticoduodenectomies, 58 (38%) of which were considered high risk for developing clinically significant pancreatic fistula. Among these, 4 (2.6%) developed a grade B or C fistula: 2 in the pasireotide group [3.5%, 95% confidence interval (CI) 0.4-11.9%], 1 in the low-risk group (1.2%, 95% CI 0.0-6.4%; difference: 2.3%, 95% CI -6.4-17.3%) and 1 in the discontinued group (10%).. We found similar rates of CR-POPF among high- and low-risk patients undergoing pancreaticoduodenectomy when using prophylactic perioperative pasireotide in high-risk patients.

Topics: Aged; Female; Humans; Male; Neuroendocrine Tumors; Pancreatic Cyst; Pancreatic Ducts; Pancreatic Fistula; Pancreatic Neoplasms; Pancreaticoduodenectomy; Postoperative Complications; Somatostatin

Signaling through mTOR and somatostatin pathway is implicated in thyroid cancer development.. We evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction.. Both everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo. Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048).. Our findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Everolimus; Female; Humans; Mice, SCID; Neuroendocrine Tumors; Proto-Oncogene Proteins c-akt; Rats, Nude; Receptors, Somatostatin; Somatostatin; Thyroid Neoplasms; TOR Serine-Threonine Kinases

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Chromogranin A; Drug Synergism; Everolimus; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Somatostatin; Stomach Neoplasms; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/-) mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/-) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/-) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.

Topics: Alleles; Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Disease Progression; Female; Mice; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Somatostatin

Early and precise delineation of therapeutic responses are key issues in neuroendocrine neoplasm/tumor management. Imaging is currently used but exhibits limitations in sensitivity and specificity. The utility of biomarkers is unclear. objective, setting, and design: This prospective cohort study (11 mo) sought to determine whether measurements of circulating neuroendocrine tumor transcripts (NETest) predict responses to somatostatin analogs (SSAs).. The test set consisted of 35 SSA-treated gastroenteropancreatic-NETs (RECISTevaluated). The prospective set consisted of 28 SSA-treated Grade 1-Grade 2 GEP-NETs.. Whole blood for transcript analysis (NETest) and plasma for Chromogranin A (CgA) (baseline), were collected every 4 weeks (prior to SSA injection). Morphologic (multidetector computed tomography/MRI) and functional imaging ((99m)Tc-[HYNIC, Tyr(3)]-Octreotide) was undertaken at entry and 6-month intervals until progression (RECIST 1.0).. Treatment response.. Test set: NETest (≥80%; scale, 0-100%) differentiated stable (SD) and progressive (PD) disease (P < .0001). Prospective set: 28 patients (26/28 SD) undergoing standard SSA. Grading: 12 G1, 16 G2. SSA Response: progression-free survival: 315 days: 14 (50%) SD, 14 (50%) PD. NETest: Twenty had elevated (≥80%) values; 14 developed PD; six, SD. CgA: Twelve of 28 exhibited elevated baseline values and/or subsequent >25% increase; eight developed PD; four, SD. NETest (P = .002) and grade (P = .054) were the only factors associated with treatment response. Multiple regression analysis established that the NETest could predict disease progression (P = .0002). NETest changes occurred significantly earlier (146 d prior to progression vs 56 d CgA; P < .0001; χ(2) = 19) and in more patients (100 vs 57%; P < .02).. NETest values (80-100%) were more accurate and occurred at a significantly earlier time point than CgA and predicted SSA treatment response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Chromogranin A; Cohort Studies; Cross-Sectional Studies; Digestive System Neoplasms; Drug Monitoring; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Prospective Studies; Somatostatin; Survival Analysis; Tumor Burden

The somatostatin receptor 2 (sst2) is the pharmacological target of somatostatin analogs that are widely used in the diagnosis and treatment of human neuroendocrine tumors. We have recently shown that the stable somatostatin analogs octreotide and pasireotide (SOM230) stimulate distinct patterns of sst2 receptor phosphorylation and internalization. Like somatostatin, octreotide promotes the phosphorylation of at least six carboxyl-terminal serine and threonine residues namely S341, S343, T353, T354, T356 and T359, which in turn leads to a robust receptor endocytosis. Unlike somatostatin, pasireotide stimulates a selective phosphorylation of S341 and S343 of the human sst2 receptor followed by a partial receptor internalization. Here, we show that exchange of S341 and S343 by alanine is sufficient to block pasireotide-driven internalization, whereas mutation of T353, T354, T356 and T359 to alanine is required to strongly inhibited both octreotide- and somatostatin-induced internalization. Yet, combined mutation of T353, T354, T356 and T359 is not sufficient to prevent somatostatin-driven β-arrestin mobilization and receptor desensitization. Replacement of all fourteen carboxyl-terminal serine and threonine residues by alanine completely abrogates sst2 receptor internalization and β-arrestin mobilization in HEK293 cells. Together, our findings demonstrate for the first time that agonist-selective sst2 receptor internalization is regulated by multi-site phosphorylation of its carboxyl-terminal tail.

Topics: Amino Acid Sequence; Antineoplastic Agents, Hormonal; Arrestins; beta-Arrestins; Cell Line; Endocytosis; HEK293 Cells; Humans; Molecular Sequence Data; Neuroendocrine Tumors; Octreotide; Phosphorylation; Protein Transport; Receptors, Somatostatin; Somatostatin

Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of carcinomas that remain difficult to treat with conventional cytotoxic regimens. The 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium brought us new insights into the management of gastroenteropancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#268 and #273) that help shed light on a novel, targeted means of treating gastroenteropancreatic neuroendocrine tumors.

Topics: Antineoplastic Agents; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Treatment Outcome

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Apoptosis; Caspase 3; Caspase 7; Cell Proliferation; Cell Survival; Chromogranin A; Cyclic AMP; DNA Fragmentation; Female; Humans; Intestinal Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin; Stomach Neoplasms; Tumor Cells, Cultured

Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of malignancies, characterized by varying degrees of biological activity and metastatic potential. A common thread between this wide mix of neoplasms has remained their sensitivity to hormonal modulation with somatostatin analogues. New analogues of somatostatin have been recently introduced and are beginning to shape a different picture of how we treat and monitor for response in patients with gastroenteropancreatic neuroendocrine tumors. Here we discuss three important abstracts presented at the annual meeting of the American Society for Clinical Oncology (ASCO) 2014 (#4107, #4108, and #4111) that highlight the changing landscape of somatostatin-based therapy.

Topics: Antineoplastic Agents; Humans; Intestinal Neoplasms; Molecular Structure; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Survival Analysis; Treatment Outcome

Pasireotide (SOM230), a long-acting somatostatin analogue (LAR), has improved agonist activity at somatostatin receptors. We tested the effect of SOM230 on insulin secretion, serum glucose concentrations, tumor growth, and survival using an MEN1 transgenic mouse model.. Eight 12-month-old conditional Men1 knockout mice with insulinoma were assessed. The treatment (n = 4) and control groups (n = 4) received monthly subcutaneous injections of SOM230 or PBS. Serum insulin and glucose levels were determined by enzyme-linked immunosorbent assay and enzymatic colorimetric assay, respectively. Tumor activity, growth, and apoptosis were determined by microPET/CT scan and histologic analysis.. On day 7, there was a decrease in serum insulin levels from 1.06 ± 0.28 μg/L to 0.37 ± 0.17 μg/L (P = .0128) and a significant increase in serum glucose from 4.2 ± 0.45 mmol/L to 7.12 ± 1.06 mmol/L (P = .0075) in the treatment group but no change in the control group. Tumor size was less in the treatment group (2,098 ± 388 μm(2)) compared with the control group (7,067 ± 955 μm(2); P = .0024). Furthermore, apoptosis was increased in the treatment group (6.9 ± 1.23%) compared with the control group (0.29 ± 0.103%; P = .002).. SOM230 demonstrates antisecretory, antiproliferative, and proapoptotic activity in our MEN1 model of insulinoma. Further studies of the effects of SOM230 in PNET patients with MEN1 mutations are warranted.

Topics: Animals; Apoptosis; Blood Glucose; Insulin; Mice; Mice, Knockout; Multimodal Imaging; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Positron-Emission Tomography; Somatostatin; Tomography, X-Ray Computed

Pasireotide (SOM-230) is a small somatostatin (SST) analog that is being developed by Novartis Pharma AG for the potential treatment of acromegaly, Cushing's disease and neuroendocrine tumors; the compound is currently in phase III clinical trials for Cushing's disease. Pasireotide exhibits high binding affinity to four of the five human (h)SST receptor subtypes, with IC50 values for hSST5 > hSST2 > hSST3 > hSST1; the compound displays no affinity for hSST4. The affinity profile of pasireotide resembles the profile of endogenous SSTs--a feature that is favorable given that different tumors exhibit differing SST receptor expression profiles. Pasireotide also exhibits a longer half-life than the clinically available SST analogs octreotide or lanreotide. Thus, this compound may be a better therapeutic agent than other analogs. In phase II clinical trials, pasireotide inhibited growth hormone (GH) secretion from GH-secreting pituitary tumors, controlled symptoms associated with metastatic carcinoid tumors, and inhibited adrenocorticotropic hormone secretion in Cushing's disease. However, a major advantage for pasireotide compared with octreotide was not demonstrated. Commonly encountered side effects for the compound included mild to moderate gastrointestinal events (diarrhea, abdominal discomfort, nausea and vomiting). The efficacy of pasireotide and any potential advantage over current therapies will need to be tested or validated in larger phase III clinical trials.

Topics: Acromegaly; Animals; Drug Evaluation, Preclinical; Human Growth Hormone; Humans; Neuroendocrine Tumors; Oligopeptides; Pituitary ACTH Hypersecretion; Somatostatin; Structure-Activity Relationship