Title: Improving chemotherapy of castration-resistant prostate cancer Abstract Because prostate cancer (PCa) requires androgen for development, androgen ablation (castration) is the primary treatment for patients with late stage PCa. However, recurrent tumors arise within 2 years, whereas androgen receptor (AR) signaling has been inappropriately restored, and the disease enters a stage called castration-resistant prostate cancer (CRPC). Docetaxel is the standard treatment for CRPC patients with limited success. Therefore, it is urgent to understand mechanisms of docetaxel so novel avenues can be developed to increase its efficacy. It was recently found that the nuclear localization of AR is microtubule dynamics dependent and that the anti-tumor effect of docetaxel in CRPC is largely due to its inhibition of AR nuclear import. However, the detailed molecular mechanisms behind these intriguing observations are still elusive. The long-term goals of this study are to provide novel approaches to overcome docetaxel resistance of CRPC. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is elevated in PCa and linked to tumor grades. The objective here is to define the role of Plk1 in activating AR signaling and to examine whether its inhibition can enhance the efficacy of docetaxel in CRPC. Clip-170 and p150Glued, two regulators of microtubule dynamics, were recently identified as novel Plk1 substrates. The central hypothesis of the proposal is that Plk1-associated activity towards Clip-170 and p150Glued increases microtubule dynamics, resulting in constitutive activation of AR signaling and development of docetaxel resistance. This hypothesis will be tested by pursuing three specific aims ? (1) to test how Plk1 phosphorylation of Clip-170 and p150Glued contributes to docetaxel resistance in CRPC cells; (2) to analyze whether Plk1-associated kinase activity contributes to docetaxel resistance in CRPC in mice; and (3) to ask whether a combination of Plk1 inhibition and docetaxel is a novel avenue for treatment of CRPC. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models, culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the AR signaling and to examine how Plk1 induces docetaxel resistance in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 activates AR; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of docetaxel. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the AR signaling that is critical for generating and maintaining the CRPC phenotype.
The proposed research is relevant to public health because it focuses on discovery of novel signaling pathways that drive castration-resistant prostate cancer. These studies will establish new avenues of investigation to develop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus, the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer.
