The proposal supported by this K08 Career Development Award consists of a 5-year career development and research plan that will provide Dr. David Takeda with the skills, experience, and mentorship to transition into an independent investigator. Dr. Takeda is an instructor in the Genitourinary Oncology Division at the Dana- Farber Cancer Institute whose long-term career goal is to become a physician-scientist focused on using functional genomic studies to advance our understanding of prostate cancer in order to provide new insights into potential therapeutics. The career development plan includes mentorship under Dr. William Hahn, who is a leader in the field of functional genomics and has successfully mentored numerous junior investigators. To further enhance his career development, the mentorship plan includes collaboration with Dr. Matthew Freedman at the Dana-Farber Cancer Institute who has pioneered epigenetic approaches to studying prostate cancer, and an advisory committee consisting of leaders in the fields of epigenetics, steroid hormone receptors, and cancer genomics. The focus of this research proposal is to understand a novel mechanism of regulation of the androgen receptor (AR) in prostate cancer. Prostate cancers require AR signaling for survival and androgen targeted therapies are the most effective treatment for advanced disease. We now know that restoration of AR signaling is also the principal mechanism driving primary resistance and development of lethal castrate resistant prostate cancer, making AR an important therapeutic target in castrate resistant disease. Despite this dependency on AR signaling, our knowledge of how AR itself is regulated is limited. Through a combination of functional genomic and epigenetic studies, Dr. Takeda identified a novel enhancer element that regulates AR expression in prostate cancer. The overall research plan of this proposal is to determine the significance of this finding for understanding the biology of AR in prostate cancer.
Specific aims i nclude: 1) To determine the contribution of the AR enhancer in progression to castrate resistant disease by activating the AR enhancer in models of castrate resistant prostate cancer. 2) To elucidate the role of HOXB13 in enhancer dependent expression of AR by using genome editing and mechanistic biochemical studies. 3) To identify trans-acting factors of the AR enhancer by performing an unbiased functional genetic screen. At the completion of this proposal, these studies will demonstrate the importance of the AR enhancer in prostate cancer progression and identify critical cellular factors involved in enhancer mediated transcriptional control of AR. These results will significantly advance our understanding of AR regulation and open up new possibilities for therapeutic intervention.
Resistance to hormone targeted therapies in prostate cancer is driven by reactivating androgen receptor (AR) signaling leading to the development of lethal castrate resistant disease. This proposal builds on studies demonstrating a novel mechanism of AR transcriptional regulation in prostate cancer. Currently there are no therapies that target AR transcription, therefore understanding the biology and significance of transcriptional regulation of AR will open up new possibilities for therapeutic targeting of AR in advanced prostate cancer.
|Takeda, David Y; Spisák, Sándor; Seo, Ji-Heui et al. (2018) A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. Cell 174:422-432.e13|