# Sensitivity of Abi1/Pten null tumors to taxane and anti-androgen receptor therapy

> **NIH NIH R21** · UPSTATE MEDICAL UNIVERSITY · 2022 · $185,552

## Abstract

ABSTRACT
Prostate cancer (PCa) is the most frequently diagnosed cancer in American men and the 2nd leading cause of
male cancer-related deaths in the U.S. Indolent localized PCa is curable, but metastatic PCa is fatal.
Progression to metastatic disease is characterized by reactivation of androgen signaling including androgen
receptor (AR) function. This knowledge led to anti-androgen pathway therapy which is a mainstay for treatment
of progressive PCa. Unfortunately, patients eventually become resistant to anti-androgen therapy and the
benefit of subsequent taxane-based chemotherapy is limited to only extending patient survival for up to a year.
An urgent need for identification of novel actionable targets remains. The long-term goal of this project is to
develop better treatment strategies and rational drug therapies for precision medicine in advanced PCa. Our
previous studies demonstrated ABI1 as a bona fide PCa tumor suppressor gene. ABI1 downregulation
promotes epithelial mesenchymal transition (EMT) downstream from activation of the non-canonical WNT-
FYN-STAT3 pathway. Our published and preliminary data indicate that ABI1 downregulation, in conjunction
with loss of PTEN, is associated with high grade and metastatic PCa in a significant subset of human PCa.
Because ABI1 expression is downregulated following androgen deprivation therapy, we hypothesize that anti-
AR treatment leads to activation of the WNT-FYN-STAT3 pathway. Moreover, taxane therapies might promote
activation of the WNT pathway and potentially cause cross-pathway effects with anti-AR treatment. Our
objective is to develop a more comprehensive understanding of the contribution of ABI1 and PTEN on tumor
sensitivity to the current treatment regimen of androgen receptor (AR)-targeting agents for both castrate-
sensitive (CSPC) and resistant (CRPC) PCa, as well as druggability of the ABI1/PTEN pathway itself. Our
central hypothesis is that ABI1-deficient tumors have a low sensitivity to anti-AR agents. In addition, we
propose that ABI1-deficient tumors are sensitive to STAT3 pathway inhibitors. We propose that ABI1 is a
candidate marker of tumor sensitivity for current treatments of PCa. Using the novel Abi1/Pten null mouse and
organoid prostate models, we will assess drug sensitivity and characterize the tumor response in search for
treatment resistance targets. We aim to: 1) Determine sensitivity of Abi1/Pten null tumors to AR inhibition
(using enzalutamide) or taxane chemotherapy (using cabazitaxel) before and after androgen deprivation; 2)
determine sensitivity of Abi1/Pten null tumors to STAT3 inhibition and synergy with AR inhibition
(enzalutamide) or taxane (cabazitaxel) chemotherapy. Tumor gene expression patterns will be analyzed by
RNA-Seq. Identified drug response-pathways will be studied using organoid and xenograft models of human
metastatic PCa lacking ABI1 and PTEN genes. The expected outcome is a better understanding of ABI1 and
PTEN involvement in tumor sensitivit...

## Key facts

- **NIH application ID:** 10430168
- **Project number:** 5R21CA260381-02
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** LESZEK KOTULA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $185,552
- **Award type:** 5
- **Project period:** 2021-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430168

## Citation

> US National Institutes of Health, RePORTER application 10430168, Sensitivity of Abi1/Pten null tumors to taxane and anti-androgen receptor therapy (5R21CA260381-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10430168. Licensed CC0.

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