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 mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.
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PMID:Targeted approaches for treating advanced clear cell renal carcinoma. 1697 18

The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.
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PMID:Evolving role of novel targeted agents in renal cell carcinoma. 1792 97

Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC.
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PMID:Sunitinib, sorafenib and mTOR inhibitors in renal cancer. 1793 73

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

The RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are activated through multiple mechanisms and appear to play a major role in melanoma progression. Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma. A combination of sorafenib (4 microM) with rapamycin (10 nM) potentiated growth inhibition in all six metastatic melanoma cell lines tested. The absolute enhancement of growth inhibition rates ranged from 13.0-27.8% in different cell lines (P<0.05, combination treatment vs monotreatment). Similar results were obtained with combinations of the MEK inhibitors U0126 (30 microM) or PD98059 (50 microM) with rapamycin (10 nM). The combined treatment of melanoma cells with sorafenib and rapamycin led to an approximately twofold increase of cell death compared with sorafenib monotreatment (P<0.05) as assessed by propidium iodide staining and cell death detection ELISA. Moreover, sorafenib in combination with rapamycin completely suppressed invasive melanoma growth in organotypic culture mimicking the physiological context. These effects were associated with complete downregulation of the antiapoptotic proteins Bcl-2 and Mcl-1. Sorafenib combined with rapamycin appears to be a promising strategy for the effective treatment of melanoma and merits clinical investigation.
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PMID:Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. 1832 81

Therapeutic approaches based solely on cytokine are meanwhile no longer recommended without restrictions as the primary therapy for metastatic renal cancer due to the reduced clinical response and the promising available data regarding molecular therapy. Several randomized controlled studies have been performed since the introduction of the so-called targeted therapies for metastatic renal cancer. Substantial data relevant for drug approval are available for the multikinase inhibitors sorafenib (Nexavar) and sunitinib (Sutent), the mTOR inhibitor temsirolimus (Torisel), and the monoclonal antibody bevacizumab (Avastin) in combination with interferon-alpha. Sunitinib, temsirolimus, and bevacizumab are approved for first-line treatment, whereas sorafenib was approved for second-line treatment in Germany.Clinical trials are currently investigating the questions of optimal timing, value of neoadjuvant or adjuvant treatment, form, and sequence of the molecular targeted therapy. Experimental investigations for a better understanding of signaling pathways will preferably allow preselecting patients for an individualized therapy in metastatic renal cell cancer (RCC). The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding"targeted" therapeutics during the treatment of metastatic RCC.
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PMID:[Value of targeted therapies for renal cell cancer]. 1858 56

The effectiveness of multikinase inhibitors in first- and second-line therapy of metastatic renal cell carcinoma (RCC) has been evaluated in various clinical studies. Initial results indicate an increased response rate and a prolonged progression-free survival compared with cytokine-containing therapeutic approaches. The new multitargeted kinase inhibitors sorafenib (Nexavar/BAY 43-9006) and sunitinib (Sutent/SUO 11248) interfere mainly with vascular endothelial growth factor and platelet-derived growth factor pathways. Recently, temsirolimus, a specific inhibitor of mammalian target of rapamycin, demonstrated activity in RCC patients with poor prognosis. This review discusses the effectiveness of the most frequently used substances for systemically progressive RCC in consideration of the currently available clinical data.
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PMID:An update on the medical therapy of advanced metastatic renal cell carcinoma. 1861 63

Angiogenesis is an important factor for cancer development and progression in humans. Hereditary and sporadic renal cell carcinoma are characterized by inactivation of the Von-Hippel Lindau (VHL) gene, which results in hyperactivity of the hypoxia-inducible factor-a (HIFa). As a consequence, there is a production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, growth, and metastatic potential of renal-cell carcinoma. These data indicate that angiogenic factors are the promising therapeutic targets in this disease. Surgery can cure the patients with renal cancer if disease is diagnosed at an early stage. On the contrary, inoperable or metastatic disease is not curable. Until recently, the only drugs approved for the treatment of advanced disease were the cytokines, interferon, and interleukin. Nevertheless, only a minority of patients (about 15%) would benefited from this treatment, while the toxicity was considerable. During the last 5 years a new era of biological agents, with considerable activity has been developed and tested in clinical trials and (some of them) have been approved in USA and Europe. These agents are: Sunitinib, Bevacizumab, Sorafenib and Temserolimus. Bevacizumab is an anti-VEGF monoclonal antibody, Sunitinib and Sorafenib are multi- tyrosine kinase inhibitors (TKIs), while Temserolimus is a mTOR inhibitor. The common these in their development is the inhibition of angiogenesis, which may explain their significant activity in renal-cell carcinoma. All the agents have been proven more effective than the interferon as first or second-line treatment. This review will focus in these recent developments and the intense continuing clinical research in this field.
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PMID:Targeting angiogenesis in renal cell carcinoma. 1869 Aug 41

Protein kinases catalyse key phosphorylation reactions in signalling cascades that affect every aspect of cell growth, differentiation and metabolism. The kinases have become prime targets for drug intervention in the diseased state, especially in cancer. There are currently 10 drugs that have been approved for clinical use and many more in clinical trials. This review summarises the structural basis for protein kinase inhibition and discusses the mode of action for each of the approved drugs in the light of structural results. All but one of the approved compounds target the ATP binding site on the kinase. Both the active and inactive conformations of protein kinases have been used in strategies to produce potent and selective compounds. Targeting the inactive conformation can give high specificity. Targeting the active conformation is favourable where the diseased state has arisen from activating mutations, but such inhibitors generally target several protein kinases. Drug resistance mutations are a potential risk for both conformational states, where drug-binding regions are not directly involved in catalysis. Imatinib (Glivec), the most successful of protein kinase inhibitors, targets the inactive conformation of ABL tyrosine kinase. Newer compounds, such as dasatinib, which targets the ABL active state, have been developed to increase potency and have proved effective for some, but not all, drug-resistant mutations. The first epidermal growth factor receptor (EGFR) inhibitors in clinical use [gefitinib (Iressa) and erlotinib (Tarceva)] targeted the active form of the kinase, and this proved advantageous for patients whose cancer was caused by mutations that resulted in a constitutively active EGFR kinase domain. Newer approved compounds, such as lapatinib (Tykerb), target the inactive conformation with high potency. A further compound that forms a covalent attachment to the kinase has been found to overcome one of the major drug resistance mutations, where the effectiveness of the drug in vivo is dependent on its ability to compete successfully in the presence of cellular concentrations of ATP. Inhibitors of vascular endothelial growth factor receptor (VEGFR) kinase against cancer angiogenesis show the advantage of some relaxation in specificity. Sorafenib, originally developed as RAF inhibitor, is now in clinical use as a VEGFR inhibitor. Temsirolimus (a derivative of rapamycin) is the only example of a drug in clinical use that does not target the kinase ATP site. Instead rapamycin, when in complex with the protein FKBP12, effectively targets mTOR kinase at a site located on a domain, the FRB domain, that appears to be involved in localisation or substrate docking.
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PMID:Protein kinase inhibitors: contributions from structure to clinical compounds. 1929 66

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.
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PMID:Small molecules and targeted therapies in distant metastatic disease. 1961 96


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