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)

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively. TSC is characterized by multiple tumors of the brain, kidney, heart, and skin. Tuberin and hamartin inhibit signaling by the mammalian target of rapamycin (mTOR) but there are limited studies of their involvement in other pathways controlling cell growth. Using ELT-3 cells, which are Eker rat-derived smooth muscle cells, we show that ELT-3 cells expressing tuberin (TSC2+/+) respond to platelet-derived growth factor (PDGF) stimulation by activating the classic mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase (MEK)-1-dependent phosphorylation of p42/44 MAP kinase (MAPK) with nuclear translocation of phosphorylated p42/44 MAPK. In contrast, in tuberin-deficient ELT-3 cells (TSC2-/-), PDGF stimulation results in MEK-1-independent p42/44 MAPK phosphorylation with reduced nuclear localization of phosphorylated p42/44 MAPK. Moreover, in TSC2-/- cells but not in TSC2+/+ cells, cellular growth and activation of p42/44 MAPK by PDGF requires the reactive oxygen species intermediate, superoxide anion (O2*-). Both baseline and PDGF-induced O2*- levels were significantly higher in TSC2-/- cells and were reduced by treatment with rapamycin and inhibitors of mitochondrial electron transport. Furthermore, the exogenous production of O2*- by the redox cycling compound menadione induced MEK-1-independent cellular growth and p42/44 MAPK phosphorylation in TSC2-/- cells but not in TSC2+/+ cells. Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth-promoting pathway involving mitochondrial oxidant-dependent p42/44 MAPK activation and mitogenic growth responses to PDGF.
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PMID:Platelet-derived growth factor-induced p42/44 mitogen-activated protein kinase activation and cellular growth is mediated by reactive oxygen species in the absence of TSC2/tuberin. 1632 35

Malignant gliomas are the most common form of primary brain tumors in adults. Despite advances in diagnosis and standard therapies such as surgery, radiation, and chemotherapy, the prognosis remains poor. Recent scientific advances have enhanced our understanding of the biology of gliomas and the role of tyrosine kinase receptors and signal transduction pathways in tumor initiation and maintenance, such as the epidermal growth factor receptors, platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs such as small molecular inhibitors of these receptors and signaling pathways are showing some activity in initial studies. As we learn more about these drugs and how to optimize their use as single agents and in combination with radiation, chemotherapy, and other targeted molecular agents, they will likely play an increasing role in the management of this devastating disease. This review summarizes the current results with targeted molecular agents in malignant gliomas and strategies under evaluation to increase their effectiveness.
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PMID:Targeted molecular therapy of malignant gliomas. 1586 84

Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation.
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PMID:Kinase inhibitors in the treatment of renal cell carcinoma. 1686 Sep 97

The VHL tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas (RCCs). pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. Downregulation of HIF is both necessary and sufficient for pVHL to suppress the growth of human renal carcinoma cells in preclinical models. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mammalian target of rapamycin (mTOR) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumorigenesis. Many of these targeted therapies have demonstrated significant activity in kidney cancer clinical trials and represent substantive advances in the treatment of this disease. How these agents should be combined with one another and with conventional agents is the subject of current trials.
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PMID:Molecular pathways in renal cell carcinoma--rationale for targeted treatment. 1704 88

The understanding of cellular processes underlying tumour biology has allowed the development of novel molecular-targeted drugs with optimistic results in renal cell carcinoma (RCC). Mutations in the von Hippel-Lindau gene are found in 75% of sporadic RCCs, which results in upregulation of several genes involved in angiogenesis, e.g. vascular endothelial growth factor and platelet-derived growth factor. Other activated pathways in RCC are the epidermal growth factor receptor and the mTOR pathway, which regulate survival and cell growth. In addition to temsirolimus (an mTOR inhibitor) two different strategies have been studied to inhibit these targets: monoclonal antibodies, e.g. bevacizumab, and small molecule tyrosine-kinase inhibitors such as sorafenib, sunitinib and AG 013736. Phase II studies with these drugs reported substantial clinical activity in advanced RCC. Survival benefit was reported with temsirolimus, sunitinib and sorafenib in randomized trials, which led to the accelerated approval of sorafenib and sunitinib for advanced RCC by regulatory authorities in the USA and Europe. Nevertheless, as new therapies develop, new challenges arise for the optimum use of these targeted drugs. We discuss the rationale and the clinical development of these novel molecular-targeted agents, with special emphasis on updated information presented at recent meetings because of the relevance of the data reported and the potential future impact in the management of patients with RCC.
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PMID:Present strategies in the treatment of metastatic renal cell carcinoma: an update on molecular targeting agents. 1709 82

In the past several years, significant advances in the underlying biological mechanisms of renal cell cancer, particularly the role of tumour angiogenesis, have permitted the design of molecularly targeted therapeutics. For this review, single-agent therapies inhibiting the following different targets were identified in the published literature: epithelial growth factor receptor, vascular endothelial growth factor receptor, basic fibroblast growth factor receptor, platelet-derived growth factor, nuclear factor-kappabeta, the mammalian target of rapamycin (mTOR) pathway, raf kinase pathway and tyrosine kinase pathway. Distinct fields of clinical research have emerged--monoclonal antibodies, small molecules, nanopeptides and immunomodulators. All therapies demonstrated acceptable toxicity profiles. Clinical benefit was assessed on the basis of the reported criteria for each study, and antitumour response (regression or delay in progression-free survival) ranged from 5% to 71%. On the basis of the limited studies to date, targeted therapies offer the greatest clinical benefit in the management of this malignancy, although additional basic research is still warranted to further improve clinical outcome.
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PMID:Targeted anti-cancer therapies for renal cancer. 1713 1

A new era is developing in the understanding of the diagnosis, classification, and management of renal-cell carcinoma (RCC). Historically, RCC has been divided into subtypes on the basis of the histopathologic findings alone. Now, genetic alterations, nuclear characteristics, and clinical criteria are routinely incorporated into the classification. The greater use of axial imaging that began in the 1980s dramatically increased the incidence of RCC, but there has not been a decrease in the percentage of cases that are metastatic. Nevertheless, many incidental lesions prove to be benign, so there is renewed enthusiasm for biopsy before treatment is selected. Genetic conditions associated with RCC, such as Von Hippel Lindau and Birt-Hogg-Dube syndromes, along with genetic analyses of tumors, have provided considerable insight into the pathogenesis of these lesions. Renal-cell carcinoma is resistant to chemotherapy, and high-dose interleukin-2 is the only regimen currently approved by the Food and Drug Administration for the treatment of advanced RCC. Stem cell transplantation is an evolving therapy. The vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor-alpha pathways are promising targets for medical therapy of RCC. Bevacizumab, a monoclonal antibody that acts as a competitive blocker of the VEGF receptor; sorafenib, an oral well-tolerated tyrosine kinase inhibitor that blocks the intracellular second-messenger system associated with the VEGF receptor; sunitinib, a multitarget inhibitor of kinases associated with the VEGF and PDGF receptors; temsirolimus (CCI-779), a kinase blocker that inhibits the mammalian target of rapamycin pathway; and erlotinib, an inhibitor of the tyrosine kinases associated with the EGF receptor, have shown promise. Combinations of the above therapies and cytokines also are being investigated, as there may be synergistic effects.
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PMID:Update on the epidemiology and biology of renal cortical neoplasms. 1720 87

The treatment of advanced renal cell carcinoma (RCC) has undergone a major change with the development of potent angiogenesis inhibitors and targeted agents. Several multitargeted tyrosine kinase inhibitors, sorafenib and sunitinib, have already been approved for the treatment of advanced RCC. Temsirolimus (CCI-779), a mammalian target of rapamycin inhibitor, has shown a survival advantage over IFN in advanced, poor-prognosis RCC patients. Bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF) A, has also shown promising clinical activity. Benefits attributable to these agents have been recognized by high objective response rates (sunitinib), significant increases in progression-free survival (sunitinib, sorafenib and bevacizumab), or improved overall survival (temsirolimus). These agents mediate much of their effect through inhibition of the hypoxia-inducible factor (HIF)-VEGF-VEGF receptor axis. Their inhibitory activity for the signaling of platelet-derived growth factor (PDGF) receptor beta or kinases like c-Raf may contribute to the antitumor effects of the multitargeted kinase inhibitors. Nevertheless, all four single agents rarely, if ever, induce complete responses and, at present, all patients develop resistance and, ultimately, progress during therapy. A critical need exists to develop strategies that may increase the degree of the antitumor effects with the hope of inducing more complete responses impeding the onset of or elimination of refractory disease. Combinations of these and other targeted agents may overcome the resistance that develops with single-agent therapy and could be incorporated either as part of initial therapy or later when disease resistance develops. Approaches aimed at combining these agents can be based on the genetics and biology of clear cell RCC. von Hippel-Lindau loss leads to an increase in cellular levels of HIF (HIF-1alpha or HIF-2alpha) leading to increased expression of a number of hypoxia-regulated genes critical to cancer progression. Combinations of targeted agents may block several of these mediators (VEGF, epidermal growth factor receptor, and PDGF), so-called horizontal blockade. Blockade could also take place at two levels of the pathways (vertical blockade), either at HIF and VEGF or at VEGF and VEGF receptor signaling. Many of the above strategies are ongoing and will require careful phase 1 determination of toxicity and even more rigorous phase 2 analysis before moving onto phase 3 trials.
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PMID:Opportunities and obstacles to combination targeted therapy in renal cell cancer. 1725 7

Phosphatidylinositol 3-kinases (PI3Ks) constitute important regulators of signaling pathways. The PIK3CA gene encoding the p110-alpha catalytic subunit represents one of the highly mutated oncogenes identified in human cancer. Here, we report new markers for in vivo PI3K activation in prostate. To that end, we used a transgenic mouse line, which expresses a constitutively active p110-alpha subunit in the epithelial cells of the prostate. The activity of the PI3K pathway in the prostate was proven by assessing the phosphorylation of the PI3K direct target AKT1 and of the mTOR target eukaryotic translation initiation factor 4G (eIF4G). To establish also transcriptional ('late') targets of the PI3K pathway, we tested two genes, Mst1 and RanBP2, which we recently described as transcriptional targets of the growth factor platelet-derived growth factor-beta. We show that the levels of both proteins are elevated in transgenic animals. Additionally, we describe that the phosphorylation of AKT and eIF4G, as well as the elevation of the Mst1 and RanBP2 protein levels, can be inhibited in vivo in transgenic animals by the PI3K inhibitor LY294002. Finally, we performed human tissue microarray experiments with the four markers. Since they define overlapping but not identical subsets of the tested tissue panel, a combination of all four markers might lead to a more accurate diagnosis of the status of the PI3K-signaling cascade in cancer patients.
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PMID:Mst1, RanBP2 and eIF4G are new markers for in vivo PI3K activation in murine and human prostate. 1737 72

In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.
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PMID:Drug insight: advances in renal cell carcinoma and the role of targeted therapies. 1765 52


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