Title: Targeting a Splicing-mediated Resistance Mechanism in Prostate Cancer Background: The androgen receptor (AR) is a transcription factor that regulates gene expression and is a common target in prostate cancer. Anti-androgen therapies are commonly used to treat androgen-dependent prostate cancer and exert their effect by antagonizing the androgen receptor (AR) at its ligand binding site, or by inhibiting androgen synthesis. Advanced prostate cancer can acquire resistance to anti-androgen treatments through a variety of mechanisms. One such mechanism is the production of AR isoforms that lack their ligand binding domain, the binding site of the receptor?s natural ligands. This results in a constitutively active transcription factor capable of promoting tumor growth in an androgen-independent manner. One such isoform, androgen receptor variant 7 (AR-V7), has been clinically observed and renders current anti-androgen therapies ineffective. The AR-V7 isoform is the result of alternative splicing of the pre-mRNA by the spliceosome during AR gene expression. The biological activity of the AR-V7 isoform has been widely studied, however the signaling pathway that leads to AR alternative splicing, and consequently the AR-V7 isoform, is not well understood. Objective and Approach: Our preliminary studies indicate that specific kinases regulate transcription and spliceosome-recruitment along the AR gene and directly influence AR pre-mRNA splicing. Our lab has a strong background in elucidating kinase signaling pathways. We therefore propose to inhibit AR-V7 splicing and elucidate the mechanism of its occurrence by employing small molecule inhibitors and genetic manipulation in a chemical genetics approach. Additionally, we will utilize chromatin profiling techniques to elucidate epigenetic regulation of the AR gene.
Specific Aims : (1) Re-programming the recruitment of the spliceosome to the androgen receptor gene; (2) Elucidating the mechanism of androgen receptor variant 7 splicing; (3) In vivo analysis of a candidate small molecule therapy. Training and Environment: The research training plan will be performed as a member of the Shokat lab at UCSF, a lab that has extensively profiled the kinome by pioneering many kinome evaluation techniques and identifying much of the known kinase-substrate interactions. Prof. Kevan Shokat is an excellent mentor for the training of graduate student and postdoctoral researchers and is a highly respected and renowned expert on the kinome. The sponsoring institution, UCSF, is a highly collaborative and innovative environment prominent for training scientists at the interface of biology and chemistry.
Title: Targeting a Splicing-mediated Resistance Mechanism in Prostate Cancer Advanced prostate cancer progresses through a variety of mechanisms and poses significant therapeutic challenges. One mechanism of growth is through alternative splicing of the androgen receptor which results in a truncated and constitutively active form of the receptor. This proposal focuses on elucidating therapeutic targets for the inhibition of androgen receptor alternative splicing.
