Article

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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    • "Moreover, whereas the synthesis of paclitaxel relies on 10-deacetylbaccatin III which is available from the needles of various Taxus species (Cragg et al., 2009), total synthesis of patupilone B has been accomplished (Su et al., 1997). The progress of epothilones in the PC setting has been extensively reviewed (Lee & Kelly, 2009, Lassi & Dawson, 2010, Cheng et al., 2008, Bystricky & Chau, 2011). Patupilone inhibits the proliferation of DU145 and TSU-Pr1 PC cells in the low nanomolar range causing mitotic arrest (Sepp-Lorenzino et al., 1999). "
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    • "Many aspects of prostate cancer research have been summarized in recent reviews that address a range of topics related to AR signaling and clinical management of the disease. These include the development of inhibitors that target steroid metabolic pathways [Lassie and Dawson, 2010; Reid et al. 2010; Attard et al. 2009] based on evidence that castration-recurrent prostate cancer cells acquire the ability to synthesize androgen [Locke et al. 2008; Montgomery et al. 2008; Stanbrough et al. 2006; Titus et al. 2005b; Mohler et al. 2004], therapeutic and vaccine approaches [Cha and Fong, 2010; Stavridi et al. 2010; Chi et al. 2009; Vis and Schröder, 2009], molecular mechanisms that underlie prostate cancer progression [Dutt and Gao, 2009], and the role of AR mutations [Brooke and Bevan, 2009], epigenetic mechanisms [Schulz and Hoffmann, 2009] and AR coregulators in prostate cancer progression [Golias et al. 2009; Heemers and Tindall, 2007]. "
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    ABSTRACT: The androgen receptor (AR) is a key transcriptional regulator and therapeutic target in prostate cancer. During androgen deprivation therapy to treat metastatic prostate cancer, surviving cells acquire increased AR signaling through a variety of mechanisms, one of which is enhanced interactions with AR coactivators. One recently identified AR-specific coregulator expressed only in human and nonhuman primates is the melanoma antigen gene protein-A11 (MAGE-11). MAGE-11 increases AR transcriptional activity through direct interactions with AR and other coactivators, and its levels increase during prostate cancer progression to castration-recurrent growth. The MAGE-11 gene is located at Xq28 on the human X chromosome as part of an X-linked MAGE gene family of cancer-testis antigens. MAGE-11 stabilizes AR when androgen levels are low, and functions in a transcriptional hub to promote AR-mediated gene activation. The evolutionary development and organization of the MAGE-11 gene within the cancer-testis antigen family suggests that MAGE-11 provides a gain-of-function to AR among primates in both normal physiology and cancer, and may serve as a therapeutic target in the treatment of advanced prostate cancer.
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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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