sirolimus and lanreotide

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

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

The present review summarizes the existing knowledge on polycystic liver disease (PCLD) and highlights the progress made in medical treatment for this condition in the past year.. PCLD is associated with autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant PCLD. Signaling pathways of adenosine 3',5'-cyclic monophosphate (cAMP) and mammalian target of rapamycin (mTOR) are aberrantly regulated in polycystic livers and promote hepatic cystogenesis. Somatostatin analogues reduce intracellular cAMP, and this might prevent fluid accumulation in hepatic cysts. Several clinical trials published over the last year now show that somatostatin analogues when given for 6-12 months in patients with ADPKD and PCLD decrease total liver volume, attenuate polycystic kidney volume, and improve perception of health. In two recent studies mTOR inhibitors failed to halt the progression of ADPKD. It is still too early to recommend to start somatostatin analogues in PCLD and definitive answers should come from future clinical trials.. Somatostatin analogues are promising new medical drug options in the treatment of PCLD. However, more needs to be elucidated with regard to molecular mechanisms in hepatic cystogenesis, the uncertainty who will respond to therapy and long-term outcomes.

Topics: Antineoplastic Agents; Cysts; Everolimus; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Liver Diseases; Octreotide; Peptides, Cyclic; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Topics: Animals; Calcium-Binding Proteins; Caroli Disease; Cholangiopancreatography, Magnetic Resonance; Cysts; Disease Models, Animal; Elasticity Imaging Techniques; Glucosidases; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Liver Cirrhosis; Liver Diseases; Magnetic Resonance Imaging; Membrane Proteins; Molecular Biology; Molecular Chaperones; Octreotide; Peptides, Cyclic; Polycystic Kidney Diseases; Prevalence; RNA-Binding Proteins; Sirolimus; Somatostatin; Tomography, X-Ray Computed

To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.

Topics: Apnea; Child, Preschool; Congenital Hyperinsulinism; Diabetes Mellitus; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Agents; Heterozygote; Homozygote; Humans; Hypoglycemia; Infant; Infant, Newborn; Lethargy; Male; Mutation; Octreotide; Oman; Pancreatectomy; Peptides, Cyclic; Postoperative Complications; Retrospective Studies; Seizures; Sirolimus; Somatostatin; Sulfonylurea Receptors; Treatment Outcome

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

In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.

Topics: Acromegaly; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Antineoplastic Agents; Biopterins; Carbapenems; Child; Child, Preschool; Cyclohexanes; Doripenem; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epothilones; Humans; Infant; Maraviroc; Peptides, Cyclic; Pharmaceutical Preparations; Phenylketonurias; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sirolimus; Somatostatin; Triazoles

Small intestinal carcinoids (SICs) are the most prevalent gastrointestinal carcinoid and characterized by local invasion metastasis and protean symptomatology. The proliferative and secretory regulation of the cell of origin, the enterochromaffin (EC) cell has not been characterized. The absence of either a pure preparation of normal EC cells or human EC carcinoid cell lines has hindered the development of therapeutic agents. We therefore further characterized the neoplastic SIC cell line, KRJ-I by assessing its secretory (serotonin (5-HT)) and proliferative responses and defining its log growth phase transcriptome. Electron microscopy demonstrated oval, lobulated nuclei and substance P, and 5-HT-positive cytoplasmic vesicles. RT-PCR detected transcripts for chromogranin A (CHGA), VMAT1 (SLC18A1), tryptophan hydroxylase (TPH1), substance P (TAC1), guanylin (GUCA2A), and SERT (SLC6A4). By immunohistochemistry, all cells were positive for CHGA, SERT, VMAT1, and TPH1. Transcriptome analysis (Affymetrix U133 Plus chips) identified somatostatin SSTR2/3, adrenergic alpha1C and beta1, dopamine D2, nicotinic-type cholinergic A5, A6, B1, muscarinic acetylcholine M4, and 5-HT-2A receptors. The presence of transcripts for SSTR1, SSTR2, and SSTR3 receptors was confirmed by RT-PCR and sequencing. Isoproterenol (ISO) resulted in a dose-dependent increase in intracellular cAMP (EC50=340 nM) and 5-HT (EC50=81 nM) which was completely inhibited by the cAMP antagonist 2',5'-dideoxyadenosine (10 microM). Preincubation with a SSTR agonist, lanreotide, inhibited Ip-stimulated 5-HT secretion (IC50=420 nM). Both lanreotide (10 nM) and rapamycin (50 nM) inhibited proliferation (20+/-12 and 35+/-5% respectively) in serum-free medium whereas gefitinib (1 nM-10 microM) inhibited proliferation at micromolar concentrations. KRJ-I is a neoplastic EC cell line that can be used as an in vitro model of SICs as it will allow elucidation and clarification of the secretory and proliferative mechanism(s) of neoplastic EC cells and the molecular signatures that characterize each of these responses.

Topics: Cell Line, Tumor; Enterochromaffin Cells; Humans; Neurosecretory Systems; Peptides, Cyclic; Sirolimus; Somatostatin