# Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $266,760

## Abstract

The past decade has brought the approval of several new treatment options for patients with metastatic
castration-resistant prostate cancer (mCRPC) that extend overall survival. However, there is no cure for mCRPC,
and development of novel therapeutic strategies is critical. Abiraterone and enzalutamide are two agents
targeting the androgen receptor (AR) signaling pathway that extend patient survival, confirming the notion that
AR remains a driver of mCRPC despite castrate levels of androgen ligands. Several mechanisms evolve during
progression to mCRPC and resistance to abiraterone/enzalutamide that function to maintain AR signaling. These
include amplification of AR, mutation of the ligand-binding domain of AR, and emergence of constitutively active
alternatively spliced AR variants. This suggests that methods to ablate AR expression in mCRPC and deplete
continued AR signaling may be effective in providing further survival benefit to patients. In this project, we will
evaluate two approaches to ablate AR in mCRPC: AR antisense oligonucleotides (ASOs) and AR degraders.
The AR ASO, IONIS-AR-2.5-Rx, has cleared a Phase I study and showed promising clinical responses in a heavily
pretreated mCRPC population. Importantly, IONIS-AR-2.5-Rx targets full-length, mutant, and splice variant forms
of AR. We have also undertaken a major effort to develop PROTAC (PROteolysis TArgeting Chimeric) AR
degraders that function by targeting AR protein to an E3 ubiquitin ligase. Together, we hypothesize that ablation
of AR, through ASOs or PROTAC degraders targeting AR, is a highly attractive therapeutic approach for
mCRPC, and we will test this through the following Specific Aims:
Aim 1: Evaluate IONIS-AR-2.5Rx, a next-generation AR ASO, in combination with enzalutamide in a Phase Ib/II
clinical trial for the treatment of mCRPC. Here, we will continue the clinical development of IONIS-AR-2.5-Rx by
performing a trial (ARRO-CITO) in combination with enzalutamide in chemotherapy-naïve mCRPC patients.
Molecular biomarkers of response will be identified through integrative clinical sequencing of tumors from the
trial. This Aim will provide clinical proof-of-concept for AR ablative strategies in mCRPC.
Aim 2: Develop potent, orally bioavailable AR degraders and study their mechanism of action. As a second
approach to deplete AR levels, we will develop a PROTAC AR degrader through a stepwise drug development
process and confirm its mechanism of action in vitro.
Aim 3: Evaluate AR degraders in preclinical models of prostate cancer to select a candidate for a Phase I clinical
trial in mCRPC. We will perform in vivo experiments in the first part of this Aim to assess pharmacokinetics,
pharmacodynamics, and antitumor activity of our top AR degraders. A Phase I study will then be initiated with
our lead compound in mCRPC patients, representing the first advancement of an AR degrader into clinical trials.
These studies will lead to the development of two therapeutic approaches ...

## Key facts

- **NIH application ID:** 10006870
- **Project number:** 5P50CA186786-07
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SHAOMENG WANG
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $266,760
- **Award type:** 5
- **Project period:** 2014-09-11 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006870

## Citation

> US National Institutes of Health, RePORTER application 10006870, Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer (5P50CA186786-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10006870. Licensed CC0.

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