Adaptation and clonal selection models of castration-resistant prostate cancer: Current perspective

Division of Urology, Department of Surgery, Ahmadu Bello University, Zaria, Nigeria.
International Journal of Urology (Impact Factor: 2.41). 11/2012; 20(4). DOI: 10.1111/iju.12005
Source: PubMed


Prostate cancer is a leading cause of cancer deaths in men worldwide. Management of the disease has remained a great challenge and even more so is the aggressive advanced stage with castration-resistant behavior. The mechanisms and timing of development of castration-resistant prostate cancer are unclear and remain debatable. Progression to castration-resistant prostate cancer is undoubtedly multifactorial, with a number of molecular-genetic aberrations implicated. However, a key question that remains unanswered is: when in the evolution of prostate cancer do the changes that confer castration resistance occur? Earlier attempts to address this question led to two proposed models: the "adaptation" and the "clonal selection" models. Although the prevailing hypothesis is the adaptation model, there is recent evidence in favor of the clonal selection model. Clarification of the model development of castration-resistant prostate cancer might significantly alter our diagnostic and therapeutic strategies, and potentially lead to improved outcome of management of this daunting condition. Here we review existing knowledge and current research findings addressing the timing of events in the course of prostate cancer progression to castration-resistant prostate cancer.

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    • "The mechanism of such benefit is currently unclear. Castrate-resistant clones may be present in the prostate prior to the initiation of ADT and they could be enriched through clonal selection after testosterone decline (Figure 3) (43). Animal models support the use of early local treatment to eliminate androgen-independent clones (44, 45). "
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    ABSTRACT: Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease.
    Frontiers in Oncology 12/2013; 3:293. DOI:10.3389/fonc.2013.00293
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    • "Most prostate cancers regress after androgen-deprivation or anti-androgen therapy, but the cancers eventually progress into castration-resistant prostate cancer (CRPC) [1]. Because no effective therapeutic regimens are available for CRPC, the recurrence of prostate cancer remains a major challenge for improving clinical outcome [2]. Therefore, it is needed to develop new therapeutic approach for prostate cancer. "
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    ABSTRACT: RNA activation (RNAa) is a small RNA-mediated gene regulation mechanism by which expression of a particular gene can be induced by targeting its promoter using small double-stranded RNA also known as small activating RNA (saRNA). We used saRNA as a molecular tool to examine NKX3-1's role as a tumor suppressor and tested in vitro and in vivo antitumor effects of NKX3-1 induction by saRNA. NKX3-1 saRNA was transfected into human prostate cancer cells including LNCaP, CWR22R, PC-3, CWR22RV1, DuPro, LAPC4, and DU145. The transfected cells were used for analysis of gene expression by RT-PCR and immunoblotting, proliferation, apoptosis and cell cycle distribution. PC-3 xenograft models were established in immunocompromised mice and treated with NKX3-1 saRNA. NKX3-1 saRNA induced NKX3-1 expression in different prostate cancer cell lines, resulting in inhibited cell proliferation and survival, cell cycle arrest and apoptotic cell death. These effects were partly mediated by NKX3-1's regulation of several downstream genes including the upregulation of p21 and p27, and the inhibition of VEGFC expression. Treatment of mouse xenograft prostate tumors with intratumoral delivery of NKX3-1 saRNA formulated in lipid nanoparticles significantly inhibited tumor growth and prolonged animal survival. By revealing several important target genes of NKX3-1, our findings corroborated NKX3-1's role as a tumor suppressor gene through direct regulation of the cell cycle and growth/survival pathways. This study also validated the therapeutic potential of saRNA for the treatment of prostate cancer via targeted activation of tumor suppressor genes. Prostate © 2013 Wiley Periodicals, Inc.
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