Stat5 Acts Independently of Androgen Receptor to Drive Advanced Prostate Cancer: Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer (PCa) and lacks effective therapeutic options. Progression to CRPC typically occurs within three years of initiation of androgen deprivation therapy. Recovery of androgen receptor (AR) transcriptional activity in CRPC has been attributed to various molecular mechanisms, but none have completely accounted for the transition from hormone-responsive PCa to CRPC. Recent studies, supported by the cancer stem cell theory of tumorigenesis, have implicated expansion of the prostate cancer stem cell (PCSC) subpopulation as a mechanism which may drive development of CRPC. Viability of PCSCs, which are negative for expression of AR, is sustained through signaling pathways independent of AR, predicting lack of responsiveness to androgen-based therapies. Our preliminary data demonstrate that the transcription factor Stat5, a validated therapeutic target protein in PCa, is crucial for survival of AR-negative and AR-depleted PCa cells. Stat5 depletion robustly down-regulates expression of the anti-apoptotic protein Survivin in the absence of AR, and Stat5 activation is increased in prospectively isolated PCSCs. The central hypothesis of this proposal is that active Stat5 promotes viability of PCa cells and development of lethal CRPC through AR-independent signaling pathways. The overall objectives are to 1) determine if the anti-apoptotic protein Survivin is a mediator of AR-independent, Stat5-driven survival of PCa cells; 2) determine if Stat5 is critical for prostate cancer stem cell-induced development and growth of CRPC. The first specific aim will determine mechanisms by which Stat5 up-regulates Survivin in AR-negative and AR-depleted PCa cells by qPCR, Western blotting and chromatin immunoprecipitation of Survivin following Stat5 activation or inhibition. Mechanistic studies will be employed to determine if Survivin expression rescues Stat5 inhibition-induced apoptosis in AR-negative and AR-depleted PCa cells using inducible expression of Stat5/Survivin following Stat5/Survivin depletion. The second specific aim will determine Stat5 activation levels in PCSCs prospectively isolated from PCa cells, xenograft tumors and clinical PCas, and if Stat5 inhibitors induce apoptosis of PCSCs in vitro. Most importantly, we will determine if Stat5-driven PCSCs induce development of CRPC growth in vivo using the unique CWR22Pc PCa xenograft model system, and if Stat5 inhibitors block PCSC-induced development of CRPC growth in this model system. In addition to providing mechanistic insight on the development of CRPC, the proposed studies explore Stat5 inhibition as a new first-line/adjuvant therapy for CRPC. These studies are significant and innovative because they propose the novel and unprecedented concept of Stat5 inhibition as a dual strategy capable of targeting both AR-dependent and AR-independent survival pathways, eliminating growth of CRPC regardless of AR status. This proposal represents an outstanding training experience in prostate cancer research for an MD/PhD student interested in translating basic science discoveries into therapeutic advances for improved patient outcomes.
The proposed research will investigate if Stat5, a gene regulatory protein known to mediate prostate cancer (PCa) growth and metastasis, promotes progression of PCa to an advanced, therapy-resistant stage known as 'castrate-resistant prostate cancer' (CRPC). We hypothesize that Stat5 acts independently of the major protein studied to date in PCa, the androgen receptor, to sustain 1) activation of pro-survival signaling pathways in PCa cells; 2) survival of tumor-initiating PCa stem cells responsible for development and growth of CRPC. We will investigate Stat5 inhibition as a therapeutic approach to prevent development of CRPC or eliminate CRPC using PCa cell lines, a PCa tumor model system mimicking CRPC in humans, and ex vivo organ cultures of clinical samples from PCa patients as our model systems.
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