Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, the elucidation of the molecular mechanisms underlying RCC development has led to the identification of promising targets for novel therapeutic agents. The involvement of the Von Hippel-Lindau protein pathway in clear cell RCC suggests that downstream targets of this pathway, namely, signaling through vascular endothelial growth factor (VEGF) in endothelial cells, platelet-derived growth factor (PDGF) in endothelial cells and pericytes, and the epidermal growth factor receptor (EGFR) pathway in tumor cells are all reasonable and rational therapeutic targets. A number of agents are in development that target VEGF (bevacizumab, a recombinant, humanized monoclonal antibody) or its receptor, VEGFR (PTK787, SU011248, and BAY 43-9006, all of which are small molecule inhibitors). Agents targeting EGFR also are being investigated clinically (gefitinib, cetuximab, erlotinib, and ABX-EGF). The Raf/MEK/ERK pathway is an important downstream convergence point for signaling through VEGFR, platelet-derived growth factor receptor (PDGFR), and EGFR (all have receptor tyrosine kinase activity) and also has important antiapoptotic effects, thereby providing an attractive target for intervention. In addition to inhibiting VEGFR and PDGFR-mediated angiogenic pathways, BAY 43-9006 has been shown to inhibit the Raf/MEK/ERK pathway at the level of Raf kinase. MEK-directed therapeutic approaches are also in development. Given that multiple molecular pathways are implicated in tumor cell growth, antitumor activity may be increased by using individual agents that target multiple pathways, or by combining different agents to allow vertical or horizontal inhibition of relevant pathways.
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PMID:Targeted agents for the treatment of advanced renal cell carcinoma. 1624 Apr 52

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.
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PMID:Molecular targeting therapy for renal cell carcinoma. 1685 Jan 27

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

Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC.
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PMID:Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. 1729 15

Tyrosine kinase receptors (RTKs) are a heterogeneous group of transmembrane proteins involved in signal transduction. These receptors are expressed in many different cells and regulate cellular growth, differentiation and angiogenesis. Overexpression and/or the structural alteration of different RTKs classes are generally associated to cancer and, when RTKs-mediated signal transduction pathways are abnormally activated, generate cancer growth, angiogenesis and metastatization. Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies. Sunitinib malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs, which has both direct anticancer and antiangiogenetic activity. Sunitinib targets selectively vascular endothelial growth factor, KIT, Flt3 and platelet-derived growth factor receptors and the receptor encoded by the ret proto-oncogene. This drug is used in the treatment of gastrointestinal stromal cancer (GIST) resistant to imatinib and metastatic renal cell carcinoma (RCC). In this review, we report preclinical data of sunitinib, even about synergism with chemotherapy and radiotherapy, data relative to phase III trials of sunitinib in the treatment of GIST and RCC, and we try to plan what will be future applications of sunitinib in different types of cancer, even in association to chemotherapy, radiotherapy and monoclonal antibodies.
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PMID:Sunitinib: bridging present and future cancer treatment. 1759 28

SU11248 sunitinib malate sutent is a selective inhibitor of certain protein tyrosine kinases including VEGF-R types 1-3 PDGF-R-a and -b, c-kit, and RET. Its antitumor activity may result from both inhibition of angiogenesis and direct antiproliferative effects on certain tumor types. In several phase I/II/III studies, sutent was found to be effective as second and first line treatment in metastatic renal cell carcinoma (RCC). In fact, with a 37% response rate and an additional 48% stable disease sutent became the drug of choice for first line treatment in RCC. Sutent was also effective as second line treatment in patients with gastrointestinal stromal tumors (GIST) with 8% response rate, 70% stable disease and a 20-month median survival. Prolonged stable disease was also documented in neuroendocrine tumors. In addition, a phase II study in multitreated women with breast cancer, sutent demonstrated a moderate activity with 16% clinical benefit. Finally, in non-small cell lung cancer (NSCLC) in patients' progressing on chemotherapy sutent was able to achieve a 10% response rate, a level of activity similar to those documented by other agents approved for lung cancer. The agent is being tested in other tumors with a modified schedule of dosage.
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PMID:Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma and various other solid tumors. 1794 82

Systemic therapy of metastatic kidney cancer has undergone dramatic changes over the past years. One reason for this is our increasing knowledge of different histological subtypes and associated genetic aberrations. Furthermore, signalling pathways have been identified to be relevant for tumour progression and therapeutic intervention. Until some years ago, systemic therapy for kidney cancer consisted of cytokines. In this review, new drugs for the treatment of metastatic kidney cancer are discussed. These drugs predominantly interact the VEGF, EGFR and mTOR signalling pathways. Four drugs have been studied in phase III trials and were (or will soon be) approved for treatment of metastatic kidney cancer. Additionally, many drugs are currently being tested in phase I and phase II trials. At present, the following scenarios have an impact on therapy decisions: different prognostic groups, first-line and second-line therapy, combination therapies and the impact of different histological subtypes.
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PMID:[New drugs for metastatic kidney cancer]. 1830 3

Immunotherapy results in a small overall survival advantage in metastatic renal cell carcinoma (RCC), but there is a need to develop more effective systemic therapies. Angiogenesis has an important role in the pathophysiology of RCC and vascular endothelial growth factor (VEGF) is a key mediator of this process. Sorafenib (BAY 43-9006) is a new agent belonging to a class of drugs called kinase inhibitors and inhibits the VEGF, platelet-derived growth factor (PDGF), and c-KIT receptor tyrosine kinases, amongst others. Sorafenib has shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients pretreated with immunotherapy, whilst prolonged progression-free survival in comparison with placebo in a phase 3 study has been reported. Further phase 3 trials in advanced disease are ongoing and a trial of adjuvant sorafenib therapy in RCC is planned.
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PMID:Renal cell carcinoma and the use of sorafenib. 1836 May 84

Lapatinib is an oral dual inhibitor of EGFR and HER2, the coexpression of which is associated with metastatic disease in patients with renal cell carcinoma. A recent randomized phase III trial of lapatinib versus hormone therapy was conducted in patients with cytokine-refractory metastatic renal cell carcinoma and tumors overexpressing EGFR and/or HER2. The study included 416 such patients who received either lapatinib (n = 209) or hormone therapy (n = 207). No benefit in time to progression, which was the primary end point of the study, or other clinical outcome measures, could be demonstrated for lapatinib therapy. A nonsignificant numerical advantage in time to progression was observed in patients with EGFR overexpression in the primary tumor (immunohistochemistry score 3+), suggesting that lapatinib could be of benefit in this subset of patients. This commentary emphasizes the need for further prospective studies to demonstrate the benefit of lapatinib therapy in patients with metastatic renal cell carcinoma.
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PMID:Lapatinib therapy for patients with advanced renal cell carcinoma. 1846 19

A woman diagnosed of a renal cell carcinoma in 1989 had a metastatic kidney cancer localised in subcutaneous nodules, gut and lung in 2007. Sorafenib treatment was initiated a 400 mg orally twice a day. The patient developed generalised erythematous skin eruptions and two weeks later a widespread erythematous maculopapular eruption located exclusively on the legs and arms, along with an objective response. The most likely cause of the generalised erythematous skin eruptions was considered to be sorafenib because of the close temporal relationship between exposure to the drug and onset of symptoms. Furthermore, a relationship between sorafenib skin toxicity and treatment efficacy was observed. This therapeutic efficacy of EGFR inhibitors and cutaneous side effects should be better assessed in large cohorts or trials to determine whether the skin toxicity of patients can be linked to an objective antitumour response.
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PMID:Generalised erythematous skin eruptions induced by sorafenib: cutaneous toxicity and treatment outcome. 1906 57


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