# Targeting a Splicing-mediated Resistance Mechanism in Prostate Cancer

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $51,945

## Abstract

Project Abstract
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.

## Key facts

- **NIH application ID:** 9836608
- **Project number:** 5F32CA236347-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** James Melnyk
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $51,945
- **Award type:** 5
- **Project period:** 2018-12-03 → 2020-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836608

## Citation

> US National Institutes of Health, RePORTER application 9836608, Targeting a Splicing-mediated Resistance Mechanism in Prostate Cancer (5F32CA236347-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836608. Licensed CC0.

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