pasireotide and Carcinoma--Neuroendocrine

Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.

Topics: Animals; Carcinoma, Neuroendocrine; Cell Proliferation; Dopamine; Humans; Octreotide; Peptides, Cyclic; Radiopharmaceuticals; Receptors, Somatostatin; Signal Transduction; Somatostatin; TOR Serine-Threonine Kinases

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

Topics: Apoptosis; Calcitonin; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Humans; Mutation; Neoplasm Invasiveness; Octreotide; Proto-Oncogene Proteins c-ret; Somatostatin; Thyroid Neoplasms; Tumor Cells, Cultured

A 51-year-old man with a history of metastatic medullary thyroid cancer (MTC) presented with high adrenocorticotropin (ACTH) and urinary free cortisol levels. The diagnosis of ectopic ACTH production, a rare MTC complication, was established in this patient. PET/CT using the somatostatin analogue DOTA-(Tyr)-octreotate labeled with gallium (Ga-DOTATATE) was performed, showing positive radionuclide uptake in multiple MTC metastases. After this therapy with the novel somatostatin analogue, pasireotide was initiated after which urinary free cortisol and ACTH levels decreased. The present case thus illustrates a potential theranostic use of Ga-DOTATATE PET/CT in MTC.

Topics: Adrenocorticotropic Hormone; Carcinoma, Neuroendocrine; Humans; Male; Middle Aged; Multimodal Imaging; Organometallic Compounds; Positron-Emission Tomography; Radiopharmaceuticals; Somatostatin; Thyroid Neoplasms; Tomography, X-Ray Computed

Somatostatin (SST) analogs are mainstay for controlling tumor proliferation and hormone secretion in carcinoid patients. Recent data suggest that extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation may potentiate the anti-tumor effects of SST analogs in carcinoids. Additionally, ERK1/2 phosphorylating agents have been shown to suppress biomarker expression in carcinoids. Thus, Raf-1/MEK/ERK1/2 pathway activating drugs may be synergistic with SST analogs such as pasireotide (SOM230), which may be more effective than others in its class given its elevated receptor affinity and broader binding spectrum. Here, we investigate the effects of SOM230 in combination with teriflunomide (TFN), a Raf-1 activator, in a human carcinoid cell line.. Human pancreatic carcinoid cells (BON) were incubated in TFN, SOM230 or a combination. Cell proliferation was measured using a rapid colorimetric assay. Western analysis was performed to analyze expression levels of achaete-scute complex-like 1 (ASCL1), chromogranin A (CgA), phosphorylated and total ERK1/2, and markers for apoptosis.. Combination treatment with SOM230 and TFN reduced cell growth beyond the additive effect of either drug alone. Combination indices (CI) fell below 1, thus quantifiably verifying synergy between both drugs as per the Chou-Talalay CI scale. Combined treatment also reduced ASCL1 and CgA expression beyond the additive effect of either drug alone. Furthermore, it increased levels of phosphorylated ERK1/2, cleaved poly(ADP)-ribose polymerase and caspase-3, and reduced levels of anti-apoptotic biomarkers. Elevated phosphorylated ERK1/2 expression following combination therapy may underlie the synergistic interaction between the two drugs.. Since efficacy is achieved at lower doses, combination therapy may palliate symptoms at low toxicity levels. Because each drug has already been evaluated in clinical trials, combinatorial drug trials are warranted.

Topics: Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Proliferation; Chromogranin A; Crotonates; Dose-Response Relationship, Drug; Drug Synergism; Gastrointestinal Neoplasms; Humans; Hydroxybutyrates; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitriles; Pancreatic Neoplasms; Somatostatin; Toluidines

Since neuroendocrine (NE) cells play an important role in the development of castration-resistant prostate cancer (CRPC), target therapy to NE cells should be considered for treating CRPC. We investigated the effects zoledronic acid (ZOL) and two somatostatin analogs (octreotide: SMS, and pasireotide: SOM) on an NE allograft (NE-10) and its cell line (NE-CS), which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse.. We examined the in vivo effects of ZOL, SMS and SOM as single agents and their combinations on subcutaneously inoculated NE-10 allografts and the in vitro effects on NE-CS cells. Apoptosis and cell cycle activity were assessed by immunohistochemistry using TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and a Ki-67 antibody, respectively.. In vivo growth of NE-10 tumors treated with ZOL, ZOL plus SMS, or ZOL plus SOM was significantly inhibited compared to the control as a consequence of induction of apoptosis and cell cycle arrest. ZOL induced time- and dose-dependent inhibition of in vitro proliferation of NE-CS cells, but the somatostatin analogs (SMS and SOM) did not. ZOL also inhibited migration of NE-CS cells. These effects were caused by inhibition of Erk1/2 phosphorylation via impairment of prenylation of Ras.. ZOL, but not SMS or SOM, induced apoptosis and inhibition of proliferation and migration through impaired prenylation of Ras in NE carcinoma models. Our findings support the possibility that ZOL could be used in the early phase for controlling NE cells, which may trigger progression to CRPC.

Topics: Androgens; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Bone Density Conservation Agents; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diphosphonates; Disease Models, Animal; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Imidazoles; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Octreotide; Orchiectomy; Prostatic Neoplasms; ras Proteins; Receptors, Somatostatin; Somatostatin; Zoledronic Acid

Therapeutic approaches to gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still not satisfactory. A new direction in treatment options could be the novel aurora kinase inhibitor ZM447439, which was previously reported to interfere with the mitotic spindle integrity checkpoint and chromosome segregation, but does not interfere with other kinases when used up to 5 muM.. We evaluated the antineoplastic effects of ZM447439 on growth and apoptosis of the GEP-NET cell lines BON, QGP-1 and MIP-101, representing the different malignant tumor types, using standard cell biological tests as crystal violet assays, caspase activation, DNA fragmentation and cell cycle analysis.. ZM447439 dose-dependently inhibited proliferation of all three cell lines with IC(50) values in the nanomolar to low micromolar range. Moreover, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation. Furthermore, we observed cell cycle arrest at G(0)/G(1) phase as well as a block in G(2)/M transition. In addition, combined treatment with the chemotherapeutic agents streptozocin and cisplatin augmented significantly the antiproliferative effects of those agents.. Aurora kinase inhibition by ZM447439 seems to be a promising new therapeutic approach in GEP-NETs, which should be evaluated in further clinical trials.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Apoptosis; Aurora Kinases; Benzamides; Carcinoid Tumor; Carcinoma, Neuroendocrine; Cell Division; Cell Line, Tumor; Cisplatin; Doxorubicin; Drug Interactions; Drug Therapy, Combination; Fluorouracil; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Octreotide; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Quinazolines; Somatostatin; Streptozocin; Survivin; Synaptophysin