Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) was one of the first polypeptide growth factors identified that signals through a cell surface tyrosine kinase receptor (PDGF-R) to stimulate various cellular functions including growth, proliferation, and differentiation. Since then, several related genes have been identified constituting a family of ligands (primarily PDGF A and B) and their cognate receptors (PDGF-R alpha and beta). To date, PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and even angiogenesis. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein, and was recently approved for several indications in the treatment of chronic myeloid leukemia. Imatinib mesylate is also a potent inhibitor of the PDGF-R kinase and is currently being evaluated for the treatment of PDGF-responsive tumors such as prostate cancer. More clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that may describe the biologic significance of PDGF-R inhibition in vivo are needed to expand the applications that target the PDGF axis.
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PMID:Platelet-derived growth factor receptors: a therapeutic target in solid tumors. 1174 Aug 4

Novartis has launched imatinib, an inhibitor of tyrosine kinases, including Bcr-Abl, for the treatment of chronic myeloid leukemia (CML). Imatinib selectively inhibits activation of target proteins involved in cellular proliferation. It also inhibits c-KIT tyrosine kinase activity and is equally effective against both wild-type and constitutively active enzyme. Close correlation between in vitro responses to IFNalpha and imatinib suggested that it may be an alternative to IFNalpha therapy for chronic-phase CML, and the compound has the advantage that it can be administered orally. Futhermore, Bcr-Abl-expressing cells treated with imatinib undergo apoptosis. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. In February 2002, the FDA approved imatinib for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST); in September 2001, launch for the indication was expected in 2002. In November 2000, imatinib was granted Orphan Drug status in Japan for the target indication of Philadelphia chromosome-positive leukemia. By May 2001, imatinib had entered phase II trials for small cell lung cancer, prostate cancer and glioma. Imatinib has been launched in more than 35 countries, including the US, Brazil, Switzerland, Australia and the UK. By December 2001, the drug had also been launched in Japan. The drug is marketed as Gleevec (imatinib mesilate) in the US, and Glivec (imatinib) outside the US. In August 2001, Deutsche Bank estimated sales of SFr 233 million in 2001, rising to SFr 850 million in 2005; while Bear Stearns & Co predicted sales of SFr 250 million in 2001, rising to SFr 800 million in 2005.
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PMID:Imatinib. Novartis. 1205 2

Over the past 15 years, numerous signal transduction pathways have been elucidated whose dysregulation may play an important role in the growth and survival of cancer cells. The success of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), a small molecule that inhibits the activation of the BCR-Abl oncogene in the treatment of chronic myelogenous leukemia, has demonstrated how effective targeted strategies can be when properly applied. With the hope of selectively targeting other critical components of cancer growth and survival while minimizing toxicity to the host, numerous strategies have been developed to inhibit receptor tyrosine kinases for various growth factors commonly expressed by cancer cells. Success of targeted inhibitors is inherently dependent on the proper selection of patients whose tumors are dependent on these growth factor pathways. Unfortunately, in prostate cancer, such selection has been a difficult-to-impossible task to date. Because of the vast number of mutational events, it is difficult to demonstrate that any particular growth factor signaling pathway is critical. In addition, because of the type (mostly bone only) and nature (usually small foci) of metastases, limited access to tumor tissue in the advanced cancer population has hampered attempts to characterize patients by their molecular features or phenotype. This article will focus on defining alternative criteria for a rational drug target and novel study designs for testing these agents in prostate cancer. In particular, the neoadjuvant setting represents a unique opportunity for new drug development in prostate cancer. An example of a neoadjuvant study testing, imatinib mesylate, is presented to display the advantages and limitations of this study design.
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PMID:Receptor tyrosine kinases as rational targets for prostate cancer treatment: platelet-derived growth factor receptor and imatinib mesylate. 1223 Oct 66

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.
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PMID:U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. 1240 1

The platelet-derived growth factor receptor (PDGFR) is a receptor tyrosine kinase overexpressed in a subset of solid tumors and therefore is the target of drugs inhibiting this function such as imatinib mesylate (Gleevec). Thus far, drug therapy has played a limited role in the treatment of localized prostate cancer (PCa). This study characterizes PDGFR-beta expression in a wide spectrum of PCa samples to provide empirical data as part of a rational treatment strategy. A survey of five published prostate expression array studies, including 100 clinically localized PCa, did not identify tumors with increased PDGFR-beta expression level. Protein expression of PDGFR-beta, as determined by immunohistochemistry, revealed 5% of clinically localized PCa and 16% of metastatic PCa cases to show moderate or strong expression. To develop a strategy to detect patients most likely to profit from Gleevec treatment, we analyzed cDNA expression array data from 10,000 transcripts for PDGFR-beta expression and divided tumors in groups based on PDGFR-beta expression level. Performing a supervised analysis to identify potential comarkers of PDGFR-beta in PCa, we identified a set of genes whose expression was associated with PDGFR-beta status including early growth response 1 (Egr1), an upstream effector of PDGF (4.2-fold upregulation), alpha-methylacyl-CoA racemase, as well as v-Maf and neuroblastoma suppressor of tumorigenicity (both with a 2.2-fold downregulation). Taken together, this study suggests that only a small subset of PCas may be amenable to tyrosine kinase inhibitors specific for PDGFR.
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PMID:Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors. 1554 58

Prostate cancer cells metastasize to the bone where their interaction with osteoclasts and osteoblasts can lead to alterations in the structure of the bone. We determined whether the systemic administration of the bisphosphonate, zoledronate, could prevent bone lysis and halt the proliferation of human prostate cancer cells injected into the tibia of nude mice. Zoledronate did not affect the in vitro proliferation of human prostate cancer PC-3MM2 cells. The in vivo administration of zoledronate produced significant bone preservation but did not inhibit the progressive growth of PC-3MM2 cells. The systemic administration of STI571 (imatinib mesylate, Gleevec), an inhibitor of phosphorylation of the platelet-derived growth factor receptor, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. The systemic administration of zoledronate with STI571 and paclitaxel produced a significant preservation of bone structure, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. Cancer is a heterogeneous disease that requires multimodality therapy. The present data recommend the combination of a bisphosphonate agent with protein tyrosine kinase inhibitor and an anticycling drug for the treatment of prostate cancer bone metastasis.
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PMID:Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. 1586 66

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

Hungary is among the leading countries in Europe regarding the mortality and incidence of different types of tumours. Therefore, developing effective therapies is especially important in this country. Investigation of tumour formation and progression on the molecular level is required to develop possible therapeutical targets. Such targets can be proteins with tumour suppressor function, which inhibit intracellular signalling processes that under pathophysiological conditions can lead to uncontrolled cell proliferation and tumour formation. Protein e3B1/Abi-1, which belongs to the family of Abl-interactors, was isolated recently as a possible tumour suppressor. As a partner of Abl kinase, its role has been investigated in the development and progression of some types of leukemias, however, more and more experimental data suggest that it is a general suppressor protein. According to the latest results, e3B1/Abi-1 via the Ras small G-protein has an essential role in the regulation of cell proliferation, and via Rac activation it can affect actin remodelling, cell adhesion and migration. Cell proliferation is important in tumour development, while cell adhesion and migration has a role in metastasis formation. The latest results showed deletion of the gene encoding protein e3B1/Abi-1 in prostate cancer, loss of its expression during the progression of some types of leukemias, and there are data on the effect of imatinib mesylate (Gleevec or outside USA Glivec, Novartis), one of the newest drugs in leukemia treatment, on the phosphorylation of e3B1/Abi-1 as well. This report summarizes the data published on protein e3B1/Abi-1, with special interest in practical implications.
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PMID:[The role of EGF receptor-dependent e3B1/Abi1 protein as a tumor suppressor protein in malignant tumors]. 1602 98

Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway is a potentially useful therapeutic strategy in the treatment of advanced prostate cancer. However mTOR antagonists used as single agents are not likely to result in dramatic clinical responses, so that it is useful to identify prospective agents that might be useful in combination. We treated CWR22Rv1 and LNCaP prostate cancer cells with an mTOR inhibitor, rapamycin, alone, or in combination with either of two receptor protein kinase (RTK) inhibitors. We assessed the effects of these treatments on cell survival and activation of down-stream mTOR target proteins. Treatment with either PD16839, an EGFr antagonist, or imatinib mesylate (Gleevec), a PDGFr, c-kit and bcr/abl antagonist, enhanced the anti-proliferative effects of rapamycin. We therefore assessed the effects of treatment with the RTK antagonist alone and in combination with rapamycin on mTOR targeted proteins. RTK antagonists alone had no effect or paradoxically increased phosphorylation of the mTOR targeted proteins, p70 S6 kinase and ribosomal S6. In contrast, when these cells were treated with either RTK antagonist in the presence of rapamycin, there was a dramatic decrease in phosphorylation of these two mTOR-targeted proteins. These effects were not mediated through phospho-AKT. Since two separate RTK antagonists had additive antiproliferative effects in combination with an mTOR antagonist and were associated with a dramatic decrease in mTOR targeted proteins in cells with or without PTEN expression, the strategy deserves further evaluation for the treatment of prostate cancer.
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PMID:Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer. 1721 76

Chromosomal rearrangements play a causal role in haematological and mesenchymal malignancies. Importantly, the resulting gene fusions can serve as specific therapeutic targets, as exemplified by the development of imatinib (Gleevec), which specifically inhibits the BCR-ABL gene fusion product that defines chronic myeloid leukaemia. Recently, gene fusions involving the prostate-specific gene transmembrane protease, serine 2 (TMPRSS2) and members of the erythroblastosis virus E26 transforming sequence (ETS) family of transcription factors were identified in most of PSA-screened prostate cancers. In this review, we summarize the identification, characterization and detection of TMPRSS2:ETS gene fusions and their role in prostate cancer development. We also discuss the discovery of additional 5' partners that define distinct classes of ETS gene fusions based on the prostate specificity and androgen responsiveness of the 5' partner. Additionally, we also summarize conflicting reports about associations between gene fusion status and patient outcome. The specificity of ETS gene fusions in prostate cancer suggests that they may have causal roles in prostate cancer and suggest utility in prostate cancer detection, stratification and treatment.
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PMID:The discovery and application of gene fusions in prostate cancer. 1842 67


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