# The role of early oncogenic drivers in maintaining lineage fidelity in prostate cancer

> **NIH CA R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2026 · $656,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Prostate cancer (PCa) is a clinically and molecular heterogenous disease, with biologically distinct subtypes
driven by characteristic genomic alterations in both early, untreated disease and treatment resistant castration-
resistant prostate cancer (CRPC). However, whether early alterations affect fidelity to prostate lineage,
shape the specific resistance patterns that emerge with treatment, and the underlying mechanisms,
remain unclear.
We hypothesize that specific molecular features of early, untreated PCa establish distinct pathways to
progression and therapeutic resistance through transcriptional control and fidelity to luminal prostate
lineage. Preliminary data generated by our multi-institutional, multidisciplinary, collaborative group suggest
specifically that the subclass of PCa defined by recurrent mutations in SPOP maintain strong fidelity to prostate
lineage, and are therefore preferentially reliant on androgen receptor (AR) signaling and possibly resistant to
conversion to AR-indifferent subtypes of CRPC.
The overall objective of this proposal is to define the propensity of prostate cancers harboring SPOP mutations
to progress to specific subtypes of treatment resistant CRPC, and to define the mechanisms that shape these
resistance patterns. Using novel models and human prostate cancer samples, our preliminary data demonstrate
that SPOP mutation reprograms AR function, altering chromatin accessibility and transcription driven by AR and
making these cancers highly reliant on AR activity. In contrast, N-Myc induction combined with RB1-loss is a
strong driver of AR-indifferent CRPC that functions to rewire and deactivate the AR transcriptional program. Our
central hypothesis is that opposing effects on rewiring of the AR-directed epigenomic and transcriptional
programs mediate the downstream impact on biology and therapeutic sensitivity shown with SPOP mutation and
drivers of AR-indifferent disease.
This project will elucidate the

## Key facts

- **NIH application ID:** 11336354
- **Project number:** 5R01CA301637-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Christopher E Barbieri; David S. Rickman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $656,000
- **Award type:** 5
- **Project period:** 2025-06-01T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11336354

## Citation

> US National Institutes of Health, RePORTER application 11336354, The role of early oncogenic drivers in maintaining lineage fidelity in prostate cancer (5R01CA301637-02). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11336354. Licensed CC0.

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