Update on castrate-resistant prostate cancer: 2010.

Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, District of Columbia 20007, USA.
Current opinion in oncology (Impact Factor: 3.76). 02/2010; 22(3):263-7. DOI: 10.1097/CCO.0b013e3283380939
Source: PubMed

ABSTRACT Prostate cancer remains a medical dilemma and a major cause of morbidity and mortality in many western countries. It represents the most common cancer in US men, with an estimated 192 280 new cases diagnosed in 2009. The median survival for men with metastatic castrate-resistant prostate cancer is 1-2 years, with improvements in survival seen primarily with docetaxel-based therapies. The purpose of this article is to discuss developments of novel agents in the field of metastatic castration-resistant prostate cancer (CRPC), including new cytotoxic agents, immune-based therapies, circulating tumor markers and targeting agents.
During this past year, several promising approaches yielded disappointing results in the phase III setting (GVAX); nonetheless, expectations for other agents (Abiraterone, MDV3100, Zibotentan, immunotherapy agents) still remain high.
Systemic therapy options are limited in CRPC and survival benefit remains to be seen with the new therapies. Circulating tumor cells continue to provide important prognostic information and will likely become an important aspect of future clinical decision-making.

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    ABSTRACT: Over the past decade, the treatment alternatives of castration-resistant prostate cancer (CRPC) have developed significantly, especially with the revelation of the docetaxel-based chemotherapy regimes. However, despite several attempts, the median survival for men with metastatic CRPC remains as 1Á2 years. The purpose of this article is to discuss the current status and recent developments in the field of CRPC, focusing particularly on the new agents that are most encouraging. Nonetheless, there are serious improvements being made in the development of more effective antiandrogens and cytochrome P17 inhibitors (abiraterone, MDV3100), novel chemotherapy regimens, targeted therapies, and immunotherapies (sipuleucel-T). For the most part, new therapeutic agents are being combined with chemotherapy, similar to the approach taken in other tumors. However, the development of new approaches to the treatment of castration resistant prostate cancer presents many challenges that will demand collaboration and consensus building with respect to biomarkers for patient selection, clinical endpoints, and trial designs. OBJECTIVES Prostate cancer is the most common cancer in men and the second leading cause of cancer related deaths in the Western World [1]. After the introduction of a prostate specific antigen (PSA), it has become a standard method of prostate cancer screening and although the incidence of prostate cancer has increased, many patients are diagnosed with the localized disease and have excellent survival and high cure rates with standard treatments [2]. However, approximately 30%Á50% of treated patients will have a local or distant recurrence despite definitive local therapy [3]. Androgen deprivation therapy (ADT) via surgical castration or hormonal manipulation using luteinizing hormone releasing hormone (LHRH), antiandrogens, or both has become the standard treatment of patients with the metastatic disease. Although the disease initially responds to ADT, most of the patients eventually progress to a state of castration-resistant prostate cancer (CRPC). CRPC refers to prostate cancer that has progressed despite castrate levels of testosterone (B50 ng/dL or B1.7 nmol/L), has three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA2 ng/mL and the patient on antiandrogen withdrawal (AAW) for at least 4 weeks [4]. The PSA concentration increases in almost 90% of the patients and bone metastasis, substantive pain and soft tissue/lymph node metastasis are observed in 90%, 35%, and 20% of the patients, respectively [5]. Unfortunately, the majority of the patients progress to an androgen independent stage that is also termed CRPC, mostly unresponsive to further hormonal manipulations [6].
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    ABSTRACT: Gonadotropin-releasing hormone (GnRH) receptors are expressed in prostate cancer, specifically in the most aggressive stage of the tumor (castration-resistant prostate cancer, CRPC) for which the standard treatment, docetaxel-based chemotherapy, can only improve the median survival time by few months. We previously showed that GnRH agonists exert an antitumor activity in CRPC cells; however, a link between GnRH receptors and the apoptotic machinery remains to be defined. Aim of this study was to evaluate whether, in CRPC cells, GnRH agonists might affect the expression/activity of apoptosis-related proteins and might sensitize, or resensitize, cancer cells to chemotherapeutics. We demonstrated that, in p53-positive DU145 cells, GnRH agonists: a) increase the expression of the proapoptotic protein Bax; this effect is mediated by the phosphorylation (activation) of p53, triggered by the p38 MAPK; b) potentiate the antiproliferative/proapoptotic activity of docetaxel; c) resensitize docetaxel-resistant cells to the antitumor activity of the cytotoxic drug. These data indicate that GnRH agonists sensitize and, more importantly, resensitize DU145 CRPC cells to chemotherapy in a p53-dependent manner. To confirm the crucial role of p53 in the activity of GnRH agonists, experiments were performed in p53-null PC3 cells. We found that GnRH agonists fail to increase Bax expression and do not potentiate the cytotoxic activity of docetaxel. These results may provide a rationale for novel combination treatment strategies, especially for docetaxel-resistant CRPC patients expressing a functional p53 protein.
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