# Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer

> **NIH NIH R37** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $387,731

## Abstract

Project Summary / Abstract
 Prostate cancer (PCa) is a clinically heterogeneous disease, with marked variability in patient
outcomes. Striking molecular heterogeneity may underlie the variable clinical course, with distinct molecular
subtypes recently identified. However, the biologic implications and translational impact of novel subtypes are
largely undefined, and there is a critical need for new models to study the biology and therapeutic
vulnerabilities of these novel subtypes of PCa. Recurrent mutations in SPOP occur in about 10% of PCa, and
define a distinct, core molecular class of PCa. However, the mechanisms by which SPOP mutation drives
prostate tumorigenesis in vivo remain unknown.
 Using multiple novel in vitro and in vivo models of SPOP mutant PCa, preliminary data demonstrate
that SPOP mutation drives neoplasia and invasive cancer in the mouse prostate. Furthermore, preliminary
studies in models in vitro and in vivo support that SPOP mutation activates the phospho-inositide 3-kinase
(PI3K) signaling pathway, with evidence for this regulation in human PCa. Interestingly, while PI3K activation
normally downregulates androgen receptor (AR) signaling, we show that SPOP mutation interrupts this
negative feedback by upregulating AR. These results suggest that SPOP mutation activates two known critical
signaling pathways in PCa – AR and PI3K signaling. Based on these preliminary findings, we hypothesize
that SPOP mutation drives prostate tumorigenesis through coordinate regulation of AR and PI3K
signaling pathways. To address this hypothesis, we will utilize novel in vitro and in vivo models and human
PCa samples to establish the mechanistic basis of SPOP regulation of PI3K/mTOR signaling, define the
relative importance of PI3K/mTOR and AR signaling in driving formation and progression of SPOP mutant
PCa, and determine the potential for therapeutic targeting of AR and PI3K/mTOR signaling in SPOP mutant
PCa.
 This project leverages unique in vivo and in vitro model systems to study a recently discovered key
subtype of PCa. Together, these studies will establish the importance of PI3K signaling and AR signaling in
PCa driven by SPOP mutations, define the critical signaling events in SPOP mutant PCa and the broader
applicability across PCa subtypes, and provide the foundation for clinical trials targeting this subclass.

## Key facts

- **NIH application ID:** 10076799
- **Project number:** 5R37CA215040-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Christopher E Barbieri
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,731
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076799

## Citation

> US National Institutes of Health, RePORTER application 10076799, Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer (5R37CA215040-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10076799. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*