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)

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

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. It accounts for 6% of the incidence of end-stage renal disease in Europe. Over the last decade, knowledge of the pathology underlying this disease has increased rapidly. Attributing important roles to tubular cell ciliary functioning, cell proliferation and fluid secretion, subsequent alterations in levels of intracellular calcium, adenosine 3',5'-cyclic monophosphate (cAMP) and activation of a variety of cellular kinases, including mammalian target of rapamycin (mTOR), has laid out the foundations for development of potentially effective treatments. In this editorial, the possible therapeutic roles for vasopressin antagonists, rapamycin, somatostatin and roscovitine are discussed. Clinical trials have been started to investigate the efficacy and safety of these agents for treating ADPKD in humans.
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PMID:Better understanding of ADPKD results in potential new treatment options: ready for the cure? 1844 6

During late gestation, amino acids and insulin promote skeletal muscle protein synthesis. However, the independent effects of amino acids and insulin on the regulation of mRNA translation initiation in the fetus are relatively unknown. The purpose of this study was to determine whether acute amino acid infusion in the late-gestation ovine fetus, with and without a simultaneous increase in fetal insulin concentration, activates translation initiation pathway(s) in skeletal muscle. Fetuses received saline (C), mixed amino acid infusion plus somatostatin infusion to suppress amino acid-stimulated fetal insulin secretion (AA+S), mixed amino acid infusion with concomitant physiological increase in fetal insulin (AA), or high-dose insulin infusion with euglycemia and euaminoacidemia (HI). After a 2-h infusion period, fetal skeletal muscle was harvested under in vivo steady-state conditions and frozen for quantification of proteins both upstream and downstream of mammalian target of rapamycin (mTOR). In the AA group, we found a threefold increase in ribosomal protein S6 kinase (p70(S6k)) and Erk1/2 phosphorylation; however, blocking the physiological rise in insulin with somatostatin in the AA+S group prevented this increase. In the HI group, Akt, Erk1/2, p70(S6k), and ribosomal protein S6 were highly phosphorylated and 4E-binding protein 1 (4E-BP1) associated with eukaryotic initiation factor (eIF)4E decreased by 30%. These data show that insulin is a significant regulator of intermediates involved in translation initiation in ovine fetal skeletal muscle. Furthermore, the effect of amino acids is dependent on a concomitant increase in fetal insulin concentrations, because amino acid infusion upregulates p70(S6k) and Erk only when amino acid-stimulated increase in insulin occurs.
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PMID:Insulin is required for amino acid stimulation of dual pathways for translational control in skeletal muscle in the late-gestation ovine fetus. 1894 Sep 43

Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI(3)K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.
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PMID:Molecular target therapy for gastroenteropancreatic endocrine tumours: biological rationale and clinical perspectives. 1924 26

Traditional treatments for patients with advanced neuroendocrine tumors include surgical debulking, hepatic embolization, somatostatin analogues, and interferon-alpha. Patients with pancreatic neuroendocrine tumors also may benefit from treatment with the alkylating agents streptozocin or temozolomide. In recent years, several promising new approaches have been investigated in patients with advanced neuroendocrine tumors. One such approach has been the use of radiopeptide therapy targeting somatostatin receptors. Additionally, agents targeting the vascular endothelial growth factor pathway and mammalian target of rapamycin have shown preliminary evidence of activity and are currently being evaluated in large randomized studies.
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PMID:Progress in the treatment of neuroendocrine tumors. 1933 11

Neuroendocrine tumors (NETs) are considered to be rare but, during the last two decades, their incidence and prevalence has considerably increased in gastro-entero-pancreatic (GEP) NETs. Most GEP-NETs express somatostatin receptors, which could be targets for treatment. The development of somatostatin analogs for treatment of functioning NETs was a revolution in the treatment of these patients and is still a cornerstone for managing hormone-related clinical symptoms. Furthermore, somatostatin analogs have also demonstrated an anti-tumor effect, with stabilization of tumor growth over long periods of time. The development of a long-acting formulation of octreotide long-acting release (LAR) significantly improved the quality of life for patients with functioning NETs in terms of necessitating only monthly injections. The side effects are few and easily manageable. In the future, somatostatin analogs will continue to be a major treatment option for functioning NETs, but will be combined with other biologicals, such as a-interferons, mTOR inhibitors and VEGF inhibitors. A new multireceptor somatostatin analog, SOM230 (pasireotide), as well as chimeric molecules, such as dopastatin (a combination of a somatostatin analogue plus a dopamine agonist), will come into the clinical management of GEP-NETs.
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PMID:Somatostatin analog octreotide LAR in gastro-entero-pancreatic tumors. 1944 73

Amino acid (AA) administration can stimulate heat accumulation in the body, as especially found under anesthetic conditions. To test our hypothesis that marked rise in plasma insulin concentrations following AA administration plays an important role in the heat storage, we intravenously administered either a balanced AA mixture or saline over 3 h, both with and without a primed-constant infusion of somatostatin in propofol-anesthetized rats. Rats on AA but lacking marked rise in plasma insulin by somatostatin treatment failed to show: attenuation of fall in core body temperature; partial increases in oxygen consumption; and stimulated muscle protein synthesis. Furthermore, the AA's stimulatory effects on phosphorylation of mTOR, 4E-BP1, and S6K1 were partially blocked by somatostatin. Our findings strongly suggest that the marked rise in insulin following AA administration promote translation initiation activities and stimulate muscle protein synthesis, which facilitates heat accumulation in the body.
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PMID:Insulin mediates the linkage acceleration of muscle protein synthesis, thermogenesis, and heat storage by amino acids. 1952 52

Surgical excision has been the mainstay of treatment for neuroendocrine tumors of the pancreas (PNET). Compounds like streptozocin and dacarbazin have been traditionally used in inoperable cases and somatostatin to treat syndromes deriving from functional tumors. However, a lot of progress has taken place in the area of molecular characterization of these tumors, revealing activation of mammalian target of rapamycin (mTOR) and VEGF pathways. Recent data from the 2010 ASCO Gastrointestinal Cancers Symposium demonstrate antitumor activity of everolimus, an mTOR inhibitor in combination with temozolomide in a phase I/II trial and of sunitinib versus placebo in a randomized double blinded phase III trial. The role of modern biologic compounds in the treatment of PNET is not clear yet. In addition, combination of resection and transarterial chemoembolization (TACE) has been proven effective over either modality alone in the treatment of PNET metastatic to the liver in a retrospective analysis. This comes to address the problem of selecting local intervention in a metastatic disease, which has been a reasonable choice for this group of tumors in the past. Last but not least the role of Ki-67 in decision-making in PNET is being discussed.
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PMID:Neuroendocrine tumors of the pancreas: what's new. Highlights from the "2010 ASCO Gastrointestinal Cancers Symposium". Orlando, FL, USA. January 22-24, 2010. 2020 21

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as somatostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1alpha under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.
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PMID:VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K/AKT/mTOR pathway. 2038 30

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


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