# A novel targetable mechanism for castration-resistant prostate cancer

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2023 · —

## Abstract

Project Summary
 Prostate cancer is the most frequently diagnosed cancer among veteran cancer patients with more than
13,000 veterans diagnosed with prostate cancer each year. Castration-resistant prostate cancer (CRPC) is a
lethal type of prostate cancer due to developing resistance to androgen deprivation therapy and the new
generation of anti-androgen drugs (i.e. Abiraterone Acetate, and Enzalutamide). Therefore, there is an urgent
need to develop novel approaches for treatment of CRPC by understanding mechanisms leading to CRPC and
identifying new therapeutic targets.
 Aberrant Wnt/β-catenin signaling plays a critical role in resistance to anti-androgen therapies and in
CRPC. In our preliminary studies, we found that Slit/Robo GTPase activating protein 1 (srGAP1) is a potential
Wnt target gene and co-regulated by androgen receptor (AR) signaling in CRPC. In addition, we found that
multiple components of Slit/Roundabout (Robo) signaling, including srGAP1, Robo1, Slit2 and RhoA, are
amplified and overexpressed in CRPC compared to primary PCa.
 Vice versa, Slit/Robo signaling can activate Wnt/β-catenin signaling by promoting the nuclear
localization of β-catenin via Rac1 activation. We have also discovered that srGAP1 interacts with guanine
nucleotide exchange factor (GEF) family of oncogenes Vav2/Vav3 that are known to regulate nuclear levels of
androgen receptor variant 7 (AR V7 and full-length AR) and the survival of CRPC cells. Based these
observations, we hypothesize that srGAP1 plays a critical role in progression to CRPC through reciprocal
amplification of both AR and Wnt signaling.
 To test these hypotheses, we will first test the hypothesis that srGAP1 is one of the required down-
stream intermediates for progression to CRPC and for resistance to anti-androgen therapies. Second, we will
assess the functional and mechanistic importance of srGAP1 on AR and Wnt/-catenin signaling and on
biological behaviors of CRPC. Third, we will determine pathophysiological relevance of the interplay between
Slit/Robo/srGAP1, AR and Wnt signaling and whether the expression of srGAP1 will be a good predictor for
disease progression and overall survival of CRPC patients.
 We expect to define the role and mechanisms of srGAP1 in progression to CRPC, which may lead to
identification of a novel target or prognostic markers for the management of this deadly neoplasm. Therefore,
our proposed work aligns very well with priority research areas of the Department of VA---Diseases with a high
healthcare burden in the Veteran population and Precision medicine studies focused on individual treatment
response.

## Key facts

- **NIH application ID:** 10513281
- **Project number:** 5I01BX005105-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Xiaolin Zi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513281

## Citation

> US National Institutes of Health, RePORTER application 10513281, A novel targetable mechanism for castration-resistant prostate cancer (5I01BX005105-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10513281. Licensed CC0.

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