There are no effective treatments for castrate-resistant (CR) prostate cancer (PCa). The work performed during the previous funding cycle provided proof-of-concept for Stat5a/b acting as a critical survival factor for human PCa cells. Inhibition of Stat5a/b leads to extensive death of Stat5-positive human PCa cell lines and blocks prostate xenograft tumor growth in nude mice. We showed that elevated levels of nuclear Stat5a/b in PCa: 1) are associated with high histological grade, 2) predict development of CR recurrent PCa and increased risk of PCa-specific death, 3) are associated with CR PCa and distant metastases and Stat5a/b activation promotes metastatic behavior of PCa cells in vitro and in vivo. Two novel concepts emerged from the work of the previous funding cycle: 1) Synergy between Stat5a/b and androgen receptor (AR)-regulated gene transcription in PCa cells7, 2) Amplification of the Stat5a/b gene locus occurs in up to 30-40% of high grade PCas and 60% of CR PCas. Preliminary progress supports exploration of three independent mechanisms of Stat5-driven growth of CR PCa: i) Stat5a/b up-regulation of full-length AR in PCa cells, ii) Stat5a/b induction of ligand-independent constitutively active AR splice variants, and iii) Stat5a/b stimulation of PCa cell survival independently of AR through Surviving. We will test the central hypothesis: Somatically amplified Stat5a/b promotes CR growth of PCa through AR- dependent and AR-independent mechanisms, and Stat5a/b provides a therapeutic target protein and response-predictive marker for CR PCa. We will pursue three aims: 1) Determine mechanisms of Stat5a/b promotion of castrate-resistant PCa growth. 2) Determine the diagnostic and functional significance of Stat5a/b gene amplification for prostate cancer progression to CR disease and clinical outcome. 3) Determine the efficacy of therapeutic targeting of Stat5a/b pathway in CR prostate cancer. At the completion of this work, we expect to have determined whether Stat5a/b gene amplification, its AR-independent PCa growth promotion and transcriptional co- action with the full length AR and AR splice variants may represent novel mechanisms of CR growth of PCa. This is significant because pharmacological inhibitors of Jak2-Stat5a/b signaling pathway represent rapidly implementable therapeutic strategies for CR PCa. We will determine whether Stat5a/b gene amplification, alone or in combination with AR gene amplification may provide a new predictive marker for identification of patients with PCa likely to progress to CR disease and would benefit from early aggressive intervention. Furthermore, Stat5a/b gene amplification may represent a predictive marker of responsiveness to therapies targeting Jak2-Stat5 signaling pathway. The proposed research may directly impact development of new strategies for improved and individualized therapy for PCa patients.
The objective of this proposal is to explore the therapy-relevant and novel concept that somatically amplified Stat5a/b promotes growth of castrate resistant (CR) prostate cancer (PCa) through AR-dependent and AR- independent mechanisms. At the completion of this work, we expect to have determined whether Stat5a/b gene amplification, its AR-independent PCa growth promotion and transcriptional co-action with the full length AR and AR splice variants represent novel mechanisms of CR growth of PCa. This is significant since Stat5a/b activation may effectively be disrupted by pharmacological inhibitors of Jak2-Stat5a/b signaling pathway, thus providing a rapidly implementable therapeutic strategy for CR PCa. We will determine whether Stat5a/b gene amplification, alone or in combination with AR gene amplification may provide a new predictive marker for identification of patients with PCa likely to progress to CR disease and would benefit from early aggressive intervention. Furthermore, Stat5a/b gene amplification may provide a predictive marker of responsiveness to therapies targeting Jak2-Stat5 signaling pathway. In summary, the proposed research may provide new strategies for improved and individualized therapy for PCa patients.
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