# Upstream and downstream targeting of the SPOP ubiquitin signaling pathway in prostate cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $710,980

## Abstract

PROJECT SUMMARY / ABSTRACT
Prostate cancer (PCa) is a clinically and molecular heterogenous disease, with distinct subtypes. These
subtypes are associated with characteristic genomic alterations, gene expression profiles, and treatment
responses, implying truly distinct biology. We have defined one such molecular subclass of PCa characterized
by recurrent missense mutations in the ubiquitin ligase SPOP -- representing about 10-15% of PCa, in both
primary and metastatic disease. These SPOP mutant cancers display distinct biology and response to
therapies. However, other key players in the SPOP pathway influencing its action in PCa, and the
broader ability to specifically target this axis for patient benefit, remain incompletely understood.
Preliminary data generated by our multidisciplinary, collaborative group have defined novel elements of the
SPOP signaling pathway, including the upstream regulator G3BP1, and suggest that the subclass of PCa
defined by deregulation of SPOP signaling are preferentially targetable with novel therapeutic interventions.
The overall objective of this proposal is to define the mechanistic, biological, and therapeutic consequences of
alterations to the SPOP signaling pathway, including its upstream regulator G3BP1. Using novel models and
human prostate cancer samples, our preliminary data demonstrate that a novel endogenous inhibitor of the
SPOP ubiquitin ligase, G3BP1, can potentially phenocopy the oncogenic effects of SPOP mutation, and that
modulation of this effect with small molecule inhibitors can be a viable therapeutic strategy. Furthermore, we
show that modulating SPOP activity reprograms androgen receptor (AR) function through key downstream
substrates, altering chromatin accessibility and transcription driven by AR and making these cancers highly
reliant on AR activity.
This project will elucidate the molecular details underlying these phenomena through the following Aims: 1)
define the role of G3BP1-driving prostate tumorigenesis in model systems and human prostate cancer, and the
ability to target this upstream axis. 2) establish the therapeutic potential of targeting the SPOP axis by modulating
targetable downstream signaling nodes. To accomplish this, we will leverage unique, biologically and clinically
relevant model systems, novel small molecule inhibitors, innovative approaches to modulating ubiquitin ligase
signaling, and data from human prostate cancer samples. This project will define the critical dependencies in
specific subtypes of prostate cancer and broader applicability to treatment response, and provide the foundation
for precision clinical trials and novel strategies to attack this subclass of cancer.

## Key facts

- **NIH application ID:** 10999747
- **Project number:** 1R01CA287724-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Christopher E Barbieri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $710,980
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999747

## Citation

> US National Institutes of Health, RePORTER application 10999747, Upstream and downstream targeting of the SPOP ubiquitin signaling pathway in prostate cancer (1R01CA287724-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999747. Licensed CC0.

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