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)

Recent identification of the mammalian target of rapamycin (mTOR) pathway as an amino acid-sensing mechanism that regulates protein synthesis led us to investigate its role in rotavirus diarrhea. We hypothesized that malnutrition would reduce the jejunal protein synthetic rate and mTOR signaling via its target, ribosomal p70 S6 kinase (p70(S6K)). Newborn piglets were artificially fed from birth and infected with porcine rotavirus on day 5 of life. Study groups included infected (fully fed and 50% protein calorie malnourished) and noninfected fully fed controls. Initially, in "worst-case scenario studies," malnourished infected piglets were killed on days 1, 3, 5, and 11 postinoculation, and jejunal samples were compared with controls to determine the time course of injury and p70(S6K) activation. Using a 2 x 2 factorial design, we subsequently determined if infection and/or malnutrition affected mTOR activation on day 3. Western blot analysis and immunohistochemistry were used to measure total and phosphorylated p70(S6K); [(3)H]phenylalanine incorporation was used to measure protein synthesis; and lactase specific activity and villus-crypt dimensions were used to quantify injury. At the peak of diarrhea, the in vitro jejunal protein synthetic rate increased twofold (compared with the rate in the uninfected pig jejunum), concomitant with increased jejunal p70(S6K) phosphorylation (4-fold) and an increased p70(S6K) level (3-fold, P < 0.05). Malnutrition did not alter the magnitude of p70(S6K) activation. Immunolocalization revealed that infection produced a major induction of cytoplasmic p70(S6K) and nuclear phospho-p70(S6K), mainly in the crypt. A downregulation of semitendinosus muscle p70(S6K) phosphorylation was seen at days 1-3 postinoculation. In conclusion, intestinal activation of p70(S6K) was not inhibited by malnutrition but was strongly activated during an active state of mucosal regeneration.
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PMID:Intestinal ribosomal p70(S6K) signaling is increased in piglet rotavirus enteritis. 1713 69

Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.
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PMID:Temsirolimus. 1798 19

Until 2006, immunotherapy (interferon-alpha or interleukin 2) was the standard medical treatment for metastatic renal cell carcinoma (RCC), and its results were disappointing: despite a few cases of complete response with prolonged survival, median survival was one year. Better understanding of the molecular mechanisms of tumor angiogenesis, especially in clear cell carcinoma, has led to the development of multiple targeted therapies to inhibit key effectors: vascular endothelial growth factor (VEGF), VEGF receptor, and mTOR (target of rapamycin). Two inhibitors targeting several protein kinases, including the VEGF receptor, have increased progression-free survival in patients with metastatic RCC and are now commercially available: sunitinib (Sutent) as first-line treatment and sorafenib (Nexavar) as second-line treatment. These targeted therapies will certainly affect overall survival, but it is too early for any firm conclusions. Their side-effects, usually low or moderate, include asthenia, anorexia, diarrhea, hand-and-foot syndrome and hypertension. Optimal management is required to ensure prolonged exposure. Other drugs have been effective: bevacizumab (Avastin), a monoclonal antibody inhibiting VEGF, increases progression-free survival as second-line treatment, and temsirolimus (Torisel), an mTOR protein kinase inhibitor, increases overall survival in the population of patients with poor prognosis. These targeted drugs will serve as the basis for development of future therapeutic strategies.
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PMID:[Renal cell carcinoma and antiangiogenic therapies]. 1803 17

We previously showed that phosphorylation of p70 S6 kinase (p70(S6k)) in the intestine is increased during viral enteritis. In this study, we hypothesized that during rotavirus infection, oral Arg, which stimulates p70(S6k) activation, will further stimulate intestinal protein synthesis and mucosal recovery, whereas the p70(S6k) inhibitor rapamycin (Rapa) will inhibit mucosal recovery. Newborn piglets were fed a standard milk replacer diet supplemented with Arg (0.4 g x kg(-1) x d(-1), twice daily by gavage), Rapa (2 mg x m(-2) x d(-1)), Arg + Rapa, or saline (controls). They were infected on d 6 of life with porcine rotavirus. Three days postinoculation, we measured the piglets' body weight, fecal rotavirus excretion, villus-crypt morphology, epithelial electrical resistance in Ussing chambers, and p70(S6k) activation by Western blotting and immunohistochemistry. We previously showed a 2-fold increase in jejunal protein synthesis during rotavirus diarrhea. In this experiment, Arg stimulated jejunal protein synthesis 1.3-fold above standard medium, and the Arg stimulation was partially inhibited by Rapa. Small bowel stimulation of p70(S6k) phosphorylation and p70(S6k) levels were inhibited >80% by Rapa. Immunohistochemistry revealed a major increase of p70(S6k) and ribosomal protein S6 phosphorylation in the crypt and lower villus of the infected piglets. However, in Arg-treated piglets, p70(S6k) activation occurred over the entire villus. Jejunal villi of the Rapa-treated group showed inactivation of p70(S6k) and a decrease in mucosal resistance (reflecting increased permeability), the latter of which was reversed by Arg. We conclude that, early in rotavirus enteritis, Arg has no impact on diarrhea but augments intestinal protein synthesis in part by p70(S6k) stimulation, while improving intestinal permeability via a mammalian target of rapamycin/p70(S6k)-independent mechanism.
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PMID:Arginine activates intestinal p70(S6k) and protein synthesis in piglet rotavirus enteritis. 1815 99

Temsirolimus is a targeted therapy that inhibits mammalian target of rapamycin (mTOR), a central regulator of tumor cell responses to growth stimuli. Temsirolimus has a broad anticancer activity profile that impacts tumor cell growth, proliferation, and survival through its specific inhibition of mTOR. In a randomized phase III trial that enrolled previously untreated patients with advanced renal cell carcinoma (RCC) and poor prognostic features, temsirolimus significantly prolonged overall survival compared with interferon-alpha, a standard therapy (p = 0.008). Because of the results, temsirolimus was approved by the U. S. Food and Drug Administration for treatment and is considered a first-line treatment for patients with advanced RCC with poor prognostic features. Temsirolimus is administered at a flat weekly IV dose of 25 mg given over 30-60 minutes. Gastrointestinal disorders (stomatitis, anorexia, nausea, diarrhea, and vomiting), rash, fatigue, edema, infections, and dyspnea, as well as hematologic and metabolic laboratory abnormalities occur in patients receiving temsirolimus. Metabolic side effects include hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and hypophosphatemia. Most adverse reactions associated with temsirolimus can be managed medically or addressed by supportive measures. Nurses can improve patient outcomes through early recognition of side effects and prompt interventions.
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PMID:Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. 1867 30

Over the course of 15 years the use of sirolimus, a macrocyclic lactone, has evolved from an adjunct to calcineurin inhibitors (CNI) to the foundation of therapy due to the drug's unique properties: First, it displays synergistic pharmacodynamic interactions with CNI. Even among high immunologic risk patients, this regimen attenuates the risk of acute allograft rejection episodes when used in combination with cyclosporine or tacrolimus. Indeed >80% reduction in CNI exposure de novo yields better long-term renal function than full cyclosporine (CsA) doses, a useful tradeoff, despite the augmented occurrence of lymphoceles and impaired wound healing. Second, by inhibiting mammalian target of rapamycin (mTOR), it exerts profound anti-neoplastic effects reducing the incidence and mediating the regression of tumors displaying PTEN-deletions and/or Akt-activations in transplant and non-transplant patients. Third, it is relatively non-nephrotoxic although it may exacerbate that property of CNI agents. Fourth, it allows prompt withdrawal of steroid therapy. Fifth, it displays reduced rates of cytomegalovirus, and BK virus infections. The major adverse reactions can generally be controlled with countermeasure therapy. Myelosuppressive effects, which tend to be transient (unless sirolimus is combined with mycophenolic acid), are readily amenable to treatment with granulocyte colony stimulating factor for leukopenia, interleukin 11 for thrombocytopenia and erythropoietin for anemia. Combinations of statins and fibrates represent effective countermeasure therapy for hypercholesterolemia and hypertriglyceridemia, respectively. Idiosyncratic reactions include hypoxemic pulmonary toxicity, refractory edema and diarrhea. Thus, sirolimus represents the vanguard of a new class of maintenance agents for immunosuppression.
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PMID:Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine. 1910 Aug 99

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
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PMID:Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. 1956 54

There is evidence that overactivity of both mammalian target of rapamycin (mTOR) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes importantly to the progressive expansion of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of each of these proteins. Clinical AMPK activators such as metformin and berberine may thus have potential in the clinical management of ADPKD. The traditional use of berberine in diarrhea associated with bacterial infections may reflect, in part, the inhibitory impact of AMPK on chloride extrusion by small intestinal enterocytes.
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PMID:Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. 1957 Jun 18

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM. Ten patients were enrolled from April 2007 to October 2008. Median age was 55 years, four were males, seven had indolent and three aggressive SM, and six were previously treated with other agents. Median duration of therapy was 4 months (range 0.2-18). No objective responses were noted. Four patients had a short-lasting subjective improvement in symptoms for a median duration of 3 months (range 3-15). Grade 1-3 diarrhea, mucositis, and neutropenia were the most common adverse effects. No Grade 4 toxicity was noted. In conclusion, everolimus does not result in appreciable clinical activity in patients with SM.
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PMID:Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis. 2003 18

The plethora of novel agents recently approved for the management of metastatic renal cell carcinoma (RCC) has changed the therapeutic landscape in this disease. The plethora of targets some of these agents inhibit can result in a wide range of side effects. While these novel therapies can be viewed as inhibitors of angiogenesis that directly or indirectly target the vascular endothelial growth factor (VEGF) pathway, their individual mechanisms of action (MoA) are key to defining their side-effect profiles. Direct VEGF inhibition with the anti-VEGF monoclonal antibody bevacizumab, is primarily associated with side effects related to the precise inhibition of VEGF, such as proteinuria, hypertension and minor bleeding events. In contrast, non-VEGF-related side effects are observed with agents inhibiting multiple receptor tyrosine kinases (sunitinib, sorafenib, axitinib and pazopanib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus); these include diarrhoea, skin rash, stomatitis, hand-foot skin reaction, hypothyroidism, and haematological and metabolic abnormalities. This review discusses the MoA of these novel therapies and how a greater understanding of MoA may help to predict the range and type of side effects, develop combinations of agents with acceptable tolerability, enable a more rational approach to patient selection, and allow the development of effective side-effect management strategies.
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PMID:Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. 2016 17


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