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

Androgen-deprivation therapy, usually with combined androgen blockade, is standard initial treatment for advanced prostate cancer. With failure of initial treatment, as indicated by rising prostate-specific antigen (PSA) levels, second-line hormonal therapy is usually instituted. Over the past several years, it has become increasingly clear that systemic chemotherapy has an important role in hormone-refractory disease. Phase II trials have demonstrated high PSA and measurable disease response rates with taxane single-agent and combination treatments. One recent phase III trial showed that docetaxel (Taxotere)/ estramustine (Emcyt) significantly improved overall survival, progression-free survival, and PSA response rate compared with mitoxantrone (Novantrone) plus prednisone. Another phase III trial demonstrated that docetaxel given every 3 weeks plus prednisone significantly improved overall survival, PSA response rate, pain relief response rate, and quality of life compared with mitoxantrone and prednisone. On the basis of these findings, every-3-week docetaxel plus prednisone is now considered standard first-line therapy for metastatic hormone-refractory disease. There is considerable optimism that treatment can be further improved. Studies of taxane combinations with bevacizumab (Avastin), thalidomide (Thalomid), bortezomib (Velcade), antisense Bcl-2 oligonucleotide, mTOR inhibitors, epidermal growth factor receptor inhibitors, and KDR inhibitors are under way. Randomized phase III trials in progress or planned are examining docetaxel in combination with imatinib mesylate (Gleevec) or calcitriol and docetaxel/prednisone in combination with bevacizumab and an antisense clusterin compound. Other promising systemic agents include epothilones and atrasentan, and promising vaccines include Provenge, GVAX, and Prostvac.
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PMID:Recent progress in management of advanced prostate cancer. 1594 43

Since 2004 and the first improvement in overall survival in hormone refractory prostate cancer patients (HRPC) brought about by docetaxel, numerous phase II and III studies have been initiated. Considering the lack of efficacy in terms of overall survival, hormonal manipulations such as antiandrogen withdrawal, di-ethylstilbesterol or dexamethason are only indicated in "rising PSA" patients without clinical or radiological evidence of metastases. As first line treatment, the optimal chemotherapy regimen is docetaxel (75 mg/m(2) every 3 weeks) in association with prednisone (5 mg twice daily). Second line chemotherapies (mitoxantron, ixabepilon, docetaxel as a re-treatment, vinorelbin, doxorubicin...) provide modest results only in terms of progression-free survival. A phase III study of Straplatin has been prematurely interrupted. Targeted anti-angiogenic therapies have shown encouraging results in patients with metastatic localizations, and underline the need to identify target patients early through cellular markers (mTOR or EGFR overexpression) as well as the uselessness of PSA dosage to monitor efficacy. An ongoing phase III study is evaluating bevacizumab in association with docetaxel to improve overall survival. Both the Provenge vaccine and DN 101 (calcitriol) showed a survival gain of a few months in phase III studies. An ongoing EORTC phase II trial is evaluating antisense oligonucleotids in HRPC. Early introduction of docetaxel raises the issue of when to start chemotherapy as it may be relevant to initiate this treatment before the onset of hormone independence. GETUG 15 trial will try to answer this question.
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PMID:[Chemotherapy of hormonorefractory and hormonoresistant metastatic prostate cancer]. 1907 Aug 17

Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDA-approved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castration-resistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody-based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors - with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer.
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PMID:Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. 2160 64