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)

Management of renal cell carcinoma (RCC) has made considerable progress in recent years, and new emerging strategies are being developed. On the basis of the results of two randomised studies in the early 2000s, nephrectomy has now become the standard as cytoreductive surgery before embarking on systemic treatment with cytokines. Interleukin (IL)-2 and interferon were the standard treatment in metastatic RCC (MRCC) until 2006. The efficacy of these two drugs, which have now been used for >20 years in MRCC, is still controversial. On the basis of many studies, these drugs should not be given to patients with a poor prognosis. In patients with good prognostic factors, a cytokine-based regimen should remain the standard as either a high-dose IL-2 or subcutaneous regimen. In patients with intermediate risk, the results of the French Percy Quattro study encourage the use of new targeted therapies as first-line therapy. Development of targeted therapies in RCC has been necessary largely because the Von Hippel-Lindau (VHL) gene is often mutated in sporadic RCC. VHL protein abnormalities lead to accumulation of hypoxia-inducible factor (HIF)-alpha and activation of a series of genes, including vascular endothelial growth factor (VEGF), thus inducing angiogenesis. Results from many recent studies with new agents that block the VEGF pathway have been reported and offer new strategic options for patients with MRCC. Sunitinib and sorafenib, two tyrosine kinase inhibitors, improve progression-free survival in RCC compared with standard treatment and have been recently approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating HIF-alpha, improves survival in RCC patients with poor risk features. Bevacizumab, a monoclonal antibody against VEGF, has shown very promising efficacy. Overall, treatment of MRCC is currently moving from the cytokine era to the targeted agent era. However, many questions still remain regarding the efficacy of combination treatments and on the best way to achieve complete remission, which is probably the best hope of curing MRCC.
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PMID:Advanced renal cell carcinoma: current and emerging management strategies. 1754 70

Recent studies have determined that mTOR mediates the activation of the protein kinase Akt in several cell types, but little is known about the association between mTOR and Akt in vascular endothelial cells. Furthermore, the functional significance of mTOR/Akt signaling has not been characterized in the endothelium. In these studies we treated endothelial cells with the mTOR inhibitor rapamycin, and we found that it decreases Akt phosphorylation and activity, as determined by phosphorylation of its substrate glycogen synthase kinase-3. This effect of rapamycin on Akt phosphorylation could not be demonstrated in endothelial cells transfected with a rapamycin-resistant mTOR construct. Also, in the presence of rapamycin, vascular endothelial growth factor, tumor necrosis factor, and insulin failed to phosphorylate Akt, further indicating that mTOR regulates Akt activation in endothelial cells. The activation of Akt is well established to mediate pro-survival signals. In part this is mediated via the phosphorylation and inactivation of the pro-apoptotic Akt substrates Foxo1 and Foxo3a. We find that rapamycin totally blocks vascular endothelial growth factor and Akt-inducible phosophorylation of these transcription factors in endothelial cells. Furthermore, inhibition of Akt activity by rapamycin increased the number of endothelial cells undergoing apoptosis after serum withdrawal as well as after stimulation by vascular endothelial growth factor or tumor necrosis factor. Taken together these observations demonstrate first, that mTOR regulates the phosphorylation and activation of Akt in endothelial cells and, second, that a major effect of mTOR inhibition in endothelial cells is to suppress Akt-inducible pro-survival signals.
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PMID:The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. 1755 6

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
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PMID:Sirolimus (rapamycin): from the soil of Easter Island to a bright future. 1758 72

Renal cell carcinoma (RCC) is a highly vascular tumor in which a growing understanding of disease biology has been translated into clinically active systemic therapies. The most clinically developed targeted therapies in advanced RCC are those that target the vascular endothelial growth factor (VEGF) ligand or receptor (VEGFR) and therapy directed against the mammalian target of rapamycin (mTOR). Sutent and sorafenib are orally available inhibitors of the VEGFR and platelet derived growth factor receptor (PDGFR). Temsirolimus is an mTOR inhibitor that leads to G1 cell cycle arrest and may affect VEGF production. This article briefly describes the biological pathways involved in the development of RCC and the results of clinical trials using targeted therapy in metastatic RCC.
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PMID:The role of targeted therapy in metastatic renal cell carcinoma. 1761 63

Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab have improved clinical outcomes in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (VEGF Trap, lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents.
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PMID:Targeted therapy for renal cell carcinoma: a new treatment paradigm. 1763 78

Traditional therapies have offered patients with advanced gastrointestinal neuroendocrine tumors limited benefit. Selected patients with hepatic metastases may benefit from surgical debulking, embolization, or other ablative therapies. While somatostatin analogs are highly effective in controlling symptoms of hormonal secretion, they are only rarely associated with tumor regression. The clinical benefit associated with the administration of systemic agents such as interferon-alpha or cytotoxic chemotherapy is less clear, and the widespread use of such regimens has been limited by their relatively modest anti-tumor activity, as well as concerns regarding their potential toxicity. The mixed clinical results seen with these agents in neuroendocrine tumors have led to great interest in the development of novel treatment approaches for patients with advanced disease. Recent clinical studies of novel agents, particularly those targeting the vascular endothelial growth factor pathway and mammalian target of rapamycin, have demonstrated promising activity in patients with advanced neuroendocrine tumors. Ongoing randomized studies should help better define the role these and other targeted agents will play in the future treatment of patients with this disease.
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PMID:Gastrointestinal neuroendocrine tumors: a role for targeted therapies? 1763 38

The mammalian target of rapamycin (mTOR) is a controller of cell growth with multiple effects on cancer development and progression. Being closely linked to key oncogenic pathways that regulate tumor cell growth and cell cycle progression, mTOR integrates the cellular response to mitogenic and growth stimuli. Rapamycin and its analogs temsirolimus and everolimus are specific inhibitors of mTOR that exert suppressive effects on proliferation, invasion, and metastasis and induce apoptosis of tumor cells. Apart from the direct effects of mTOR inhibitors on tumor cells, rapamycin and its analogs have potent antiangiogenic properties related to the suppression of vascular endothelial growth factor signal transduction. While the use of mTOR inhibitors as a monotherapy seems to be insufficient to effectively control tumor progression in most tumor entities, combination with tyrosine kinase inhibitors or cytotoxic agents might potentiate the antitumoral effects of mTOR inhibition. In a clinical setting, mTOR inhibitors show an acceptable safety profile over a wide dose range. Currently, mTOR inhibitors are tested in multiple trials in combination with other agents in various cancer entities in intermittent schedules to avoid immunosuppression. However, lacking adequate surrogate and response parameters, the most effective biological dosing schedules remain to be defined. Considering these apparent limitations, the full clinical potential of this promising class of drugs is at risk to be missed by applying them inadequately.
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PMID:Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. 1771 40

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.
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PMID:Treatment options in renal cell carcinoma: past, present and future. 1776 20

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.
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PMID:Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. 1780 74

Metastatic renal cell cancer has traditionally been treated with interferon and interleukin-2. An improved understanding of the biology of renal cancer has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mammalian target of rapamycin signal transduction pathway in particular have been utilized as therapeutic targets. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab/interferon alfa have improved clinical outcomes in randomized trials. Other antiangiogenic agents have also demonstrated activity in early studies. Given the availability of multiple treatment options, several questions emerge as to how to integrate these new therapies into the management of metastatic renal cell cancer. Recently reported and planned clinical trials will help clarify the role of these agents. The future of therapy for renal cancer appears promising owing to the efficacy of these novel agents.
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PMID:Renal cell cancer. 1792 25


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