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

Clear-cell renal cell carcinoma is characterized by the inactivation of the von Hippel-Lindau tumor suppressor gene, which results in an overproduction of vascular endothelial growth factor that promotes tumor angiogenesis, growth, and metastasis after binding with its receptor. The mammalian target of rapamycin signal transduction pathway is involved in the translation of hypoxia inducible factor-1 and vascular endothelial growth factor. Sunitinib, sorafenib, bevacizumab, and temsirolimus have improved clinical outcomes by inhibiting these tumorigenic pathways. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. Clinical trials designed to further assess these and other agents need to be vigorously supported.
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PMID:Targeting growth factor and antiangiogenic pathways in clear-cell renal cell carcinoma: rationale and ongoing trials. 1723 82

TNFalpha has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.
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PMID:IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. 1769 55

Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial growth factor promotes tumor angiogenesis, ascites formation, and metastasis in ovarian cancer. In this study, an i.p. model of human ovarian cancer was used to determine the antitumor activity of rapamycin, bevacizumab, and rapamycin plus bevacizumab (BEV/RAPA). We report that administration of rapamycin, bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p. tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in hypoxia-inducible factor-1alpha and cyclin D1 and inactivation of downstream targets of mTOR, p70S6 kinase, S6R, and 4E-binding protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than rapamycin and bevacizumab to prevent the development of peritoneal carcinomatosis in adjuvant setting and reverse ascites accumulation in heavy peritoneal disease. Our data indicate that simultaneous inhibition of the vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of metastasis, recurrence, and treatment of ovarian cancer.
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PMID:Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer. 1802 80

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

Mammalian target of rapamycin (mTOR) is a crucial molecule in the control of cell size and proliferation; dysregulation of the mTOR pathway is commonly found in human cancers. Many cancer-promoting kinases have been identified as regulators of mTOR activity through phosphorylation and inactivation of the TSC1-TSC2 complex. Tumorassociated macrophages (TAMs) are tumor-promoting factors in inflammation-mediated tumor development, and the signaling molecules involved in TAMs-mediated tumor angiogenesis are not well understood. Therefore, it is urgent to elucidate the cross-talk between inflammatory cells and cancers and to explore the precise pathways involved in TAMsinduced tumor angiogenesis. Recently IKKbeta was found to activate the mTOR pathway and to promote tumor angiogenesis through inactivation of the TSC1-TSC2 complex by phosphorylating TSC1. This finding provides critical insights into and suggests one mechanism behind inflammation-mediated tumor angiogenesis. In this extra-view, we briefly discuss the possible influence of TAMs-released proangiogenic factors on mTOR activation and propose a model of the cross-talk between tumors and TAMs in tumor angiogenesis.
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PMID:All roads lead to mTOR: integrating inflammation and tumor angiogenesis. 1807 29

In this review, pathogenesis and genetic alterations of urologic malignancies and their therapeutic target molecule are summarized briefly. In bladder cancer, only a little has been revealed. Loss of heterozygosity of 9p/q is frequently observed in low grade, low stage tumors. In invasive or carcinoma in situ tumors, alteration of p53 and Rb tumor suppressor gene is frequently found. In prostate cancer, the process of carcinogenesis from normal epithelium to cancer hypothesized by Nelson et al. (N Engl J Med 24; 349 : 366-381) seems to be logic. Androgen independency of tumor cells is associated with androgen receptor gene mutation and amplification, however, the mechanism is not well clarified. It is a turning point, therapeutic strategy is changing from cytokine immunotherapy to molecular targeting therapy in metastatic renal cell carcinoma. The pathway from growth factors such as vascular endothelial growth factor and platelet derived growth factor, and their receptors to mTOR is a central controller of tumor angiogenesis and proliferation.
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PMID:[Tumor inhibitory factors in urologic malignancies]. 1826 Mar 61

Renal-cell carcinoma represents 95% of all renal tumours. The Von Hippel-Lindau (VHL) tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas. pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mTOR (mammalian target of rapamycin) 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 tumor angiogenesis. Many of these targeted therapies, especially sunitinib, have demonstrated significant activity in kidney cancer clinical trials and represent a substantive advance in the treatment of this disease.
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PMID:[Current strategies in the treatment of renal-cell cancer: targeted therapies]. 1838 Oct 31

Vascular endothelial growth factor (VEGF) plays a vital role in tumor angiogenesis. VEGF is produced by human melanomas, and the VEGF receptor 2 (VEGFR-2) is expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Here, we show that bevacizumab, an anti-VEGF antibody, inhibits proliferation of VEGFR-2(+) melanoma cell lines by an average of 41%; however, it failed to inhibit proliferation of VEGFR-2(neg) melanoma cell lines. The growth inhibitory effect of bevacizumab was eliminated by VEGFR-2 knockdown with small interfering RNA, showing that VEGF autocrine growth in melanoma is mediated through VEGFR-2. However, bevacizumab inhibition of autocrine signals did not completely inhibit cell proliferation nor cause cell death. Cell survival is mediated partially through mammalian target of rapamycin (mTOR), which is inhibited by rapamycin. Combination of bevacizumab with rapamycin caused loss of half of the VEGFR-2(+) melanoma cells, but no reduction in the number of VEGFR-2(neg) melanoma cells. The results show (a) an autocrine growth loop active in VEGFR-2(+) melanoma, (b) a nonangiogenic mechanism for inhibition of melanoma by blocking autocrine VEGFR-2 activation, and (c) a possible therapeutic role for combination of inhibitors of mTOR plus VEGF in selected melanomas.
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PMID:Human melanoma cytolysis by combined inhibition of mammalian target of rapamycin and vascular endothelial growth factor/vascular endothelial growth factor receptor-2. 1851 1

Soft-tissue sarcomas (STS) include a spectrum of histologically and clinically different tumors. Patients with these tumors are typically relatively young and the course of disease is characterized by early metastasis as well as limited response to chemotherapy. However, a few subtypes, such as small round-cell tumors and rhabdomyosarcoma (other than pleomorphic), are considered chemotherapy sensitive. In addition, reflecting successful translational research of recent years, gastrointestinal stromal tumor and dermatofibrosarcoma protuberans have become model diseases for targeted oncologic therapy. We summarize current treatment options for metastatic STS, including established first-line chemotherapy approaches, mainly with anthracyclines and/or ifosfamide and second-line treatment choices beyond anthracyclines. Until only a few years ago, treatment choices for metastatic STS were easy to review because of the very limited number of active compounds available. However, with the advent of novel therapeutic strategies such as the anti-angiogenic approach and a multitude of novel compounds available both outside and within clinical studies, it has potentially become more difficult to keep track of currently available treatment options for STS and their clinical safety and efficacy. In this practice-oriented article, we therefore review treatment goals in advanced STS and provide an overview of compounds with proven activity in this setting. Anthracyclines with or without ifosfamide are still considered standard of care for most STS subtypes, especially for high-grade tumors. There is no evidence-based recommendation regarding use of second-line treatment options. However, a number of established compounds, including dacarbazine/temozolomide, gemcitabine, taxanes, trofosfamide, DNA topoisomerase I inhibitors, DNA minor groove binders, and bendamustine have shown activity. Recently, trabectedin, a DNA minor groove binder initially isolated from a sea sponge, has proven effective and received European approval for use in treatment-refractory STS. In addition, novel compounds such as bevacizumab, multi-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, imatinib, and the thrombospondin agonist ABT 510 represent attractive partners for the above-mentioned cytostatic agents, or may even be effective single agents in the clinically advanced setting. Novel combinations are being evaluated in clinical studies. In order to be successful, it may be necessary to combine not only different compounds but also different targets beyond the proliferation machinery of sarcoma cells such as tumor angiogenesis, the tumor stromal compartment, or tumor cell oncogene products.
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PMID:Potential combination chemotherapy approaches for advanced adult-type soft-tissue sarcoma. 1857 72

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc(Delta716) heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. beta-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, long-term RAD001 treatment significantly reduced mortality of the Apc(Delta716) mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.
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PMID:Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. 1876 9


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