Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinoid tumors are predominantly found in the gastrointestinal tract and are characterized by hypersecretion of various substances, including bioamines and neuropeptides, leading to functional tumor disease. Here, we demonstrate that human BON carcinoid tumor cells express functionally active insulin-like growth factor-I (IGF-I) receptors and secrete IGF-I, suggesting an autocrine action of this growth factor. The IGF-I receptor was functionally active. IGF-I stimulated phosphatidylinositol 3-kinase (PI3-kinase), p70 S6 kinase (p70s6k), and extracellular signal-regulated kinase 2 activity in BON cells. Furthermore, immunoneutralization of endogenously released IGF-I markedly reduced the high basal activity of p70s6k and extracellular signal-regulated kinase 2 in serum-starved BON cells. Exogenously added IGF-I induced a marked increase in chromogranin A secretion, a marker protein for neuroendocrine secretion, by a process that was largely dependent on PI3-kinase activity. In addition, immunoneutralization of endogenously released IGF-I markedly reduced basal chromogranin A release by BON cells. Thus, the autocrine IGF-I loop regulates basal neuroendocrine secretion in BON cells. Next, we investigated the role of IGF-I as a growth promoting agent for BON cells. Our data demonstrate that IGF-I stimulates anchorage-dependent and anchorage-independent growth of BON cells by a pathway that involves PI3-kinase, mammalian target of rapamycin/p70s6k, and mitogen-activated protein kinase kinase 1 activity. Interestingly, mitogen-activated protein kinase kinase 1 activity was less important for anchorage-independent growth of BON cells. Endogenously released IGF-I was found to be largely responsible for autonomous growth of BON cells in serum-free medium and for the constitutive expression of cyclin D1 in these cells. In conclusion, IGF-I is a major autocrine regulator of neuroendocrine secretion and growth of human BON neuroendocrine tumor cells. Because our data also demonstrate that a significant proportion of neuroendocrine tumors express the IGF-I receptor and its ligand, interference with this pathway could be useful in the treatment of hypersecretion syndromes and growth of human neuroendocrine tumors.
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PMID:Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. 1096 9

Neuroendocrine tumours of the gastroenteropancreatic axis include carcinoid tumours and islet cell tumours of the pancreas (pancreatic endocrine tumours). Standard medical therapies prescribed for these malignancies include long-acting somatostatin analogues (octreotide and lanreotide) for the palliation of hormonal syndromes; cytotoxic agents (streptozocin, dacarbazine, adriamycin and 5-fluorouracil), which are primarily for the management of advanced islet cell tumours; and hepatic artery embolisation or chemoembolisation for the treatment of liver metastases. Clinical research promises to expand this therapeutic armamentarium. Most of the experimental treatments that are being evaluated in human clinical trials fall into the following categories: angiogenesis inhibitors, novel somatostatin analogues, radiolabelled somatostatin analogues, mTOR inhibitors and novel cytotoxic agents. This review summarises the present scope of clinical research in this field.
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PMID:A review of the current clinical trials for gastroenteropancreatic neuroendocrine tumours. 1724 41

Carcinoid and islet-cell carcinoma are often also known as low-grade neuroendocrine carcinomas. They are often slow-growing but can be resistant to standard therapy. While somatostatin analogues are often used to control hormonal syndromes, there is currently no therapy approved in the US for control of carcinoid tumor growth. For islet-cell carcinoma, streptozocin-based chemotherapy may induce tumor shrinkage, but second-line option are limited. This chapter reviews the molecular biology of neuroendocrine tumors, including the roles of MENIN, TSC2, NF-1, vHL, p53, bcl-2, bax, VEGF, IGF, PDGF, EGFR, and mTOR. Recently, there has been interest in developing molecularly targeted therapy for this group of diseases. Phase-II studies with imatinib, bevacizumab, sunitinib, gefitnib, temsirolimus, and everolimus (RAD001) have completed accrual. Encouraging results have been observed in studies with VEGF and mTOR inhibitors. Phase-III study of bevacizumab is planned in the US. Large-scale multinational phase-II and -III studies of everolimus are under way.
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PMID:Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. 1738 71

Although endocrine tumors are often slow growing, most can be life threatening and are considered resistant to conventional cytotoxic chemotherapy. The recent emergence of molecularly targeted therapy in oncology has brought renewed interest in the development of novel agents for this rare group of diseases. Preliminary results from phase II studies have shown promising results for VEGF and mTOR inhibitors in carcinoid and islet cell carcinoma and RET inhibitors in medullary thyroid carcinoma. Large confirmatory studies are planned.
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PMID:Molecular targeted therapy for neuroendocrine tumors. 1754 41

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.
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PMID:Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. 1831 Feb 92

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well-differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors.
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PMID:Pulmonary neuroendocrine/carcinoid tumors: a review article. 1956 72

Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.
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PMID:Sunitinib paves the way for targeted therapies in neuroendocrine tumors. 1991 Nov 11

Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.
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PMID:Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. 2038 47

Patients with well-differentiated neuroendocrine tumours of the gastrointestinal tract often present with metastases and hormonal symptoms. These patients can be palliated by interventional tumour reduction and medical treatment with somatostatin analogues; no effective chemotherapy is available. Radionuclide therapy via somatostatin receptors is one new therapeutic alternative. The recognition that neuroendocrine tumours express specific receptors for growth factors and chemokines, which are of importance for tumour growth, vascularization, and spread, may open the way for new therapeutic approaches. The signalling pathways in carcinoid tumours are incompletely explored. This review summarizes potential new treatment strategies from clinical and experimental studies, e.g. inhibition of angiogenesis, targeting of growth factors or their receptors by tyrosine kinase inhibitors, interference with specific cellular pathways (mTOR, PI3K, RAS/RAF, Notch), and also inhibition of the proteasome and histone deacetylation. Combining targeted therapy with chemotherapy, or using drugs to sensitize for radionuclide therapy, may enhance the treatment outcome.
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PMID:New medical strategies for midgut carcinoids. 2040 94

The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In contrast to the relatively conserved karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics-based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC.
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PMID:Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors. 2061 70


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