sirolimus and pasireotide

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

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

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

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

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

Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers.. The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs.. We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR.. In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter.. Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Topics: Adenoma; Aged; Apoptosis; Cabergoline; Cell Line, Tumor; Cell Survival; Ergolines; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pituitary Neoplasms; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Somatostatin; Vascular Endothelial Growth Factor A

Topics: Animals; Endocrine System Diseases; Everolimus; Humans; Immunosuppressive Agents; Oligopeptides; Protein Kinases; Receptors, Somatostatin; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases