# Dissecting Early Tumor Evolution to Uncover Mechanisms of Tumor Initiation and Drug Resistance

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $11,333

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite the prevalence of prostate cancer worldwide, we lack an understanding of the genetic events that drive
tumor initiation or drug resistance. Only a few genetic models exist, leaving hundreds of recurrent mutations
unaccounted for, and most studies interrogate gene function by overexpression or knockout rather than studying
the mutational variants present in disease. Better understanding of the mutations driving tumor initiation and
drug resistance could allow us to screen for precancerous lesions or prevent fatal disease progression, greatly
relieving the global burden of disease. Therefore, there is an urgent need for a new functional genomic approach
to enable the functional study of multiple genetic variants per cell to identify mechanisms of tumor initiation and
drug resistance. We have developed such a system in mouse prostate organoids by knocking out the tumor
suppressor Pten and the mismatch repair gene Msh2 to induce the accumulation of point mutations and indels.
This system has allowed us to interrogate which mutations complement PTEN loss to drive tumor initiation and
drug resistance in vivo. We have discovered that hotspot mutations in IRS4 and CDK4 are uniquely enriched
during tumor initiation and drug resistance, respectively. Thus, I propose to determine the mechanisms by
which IRS4 and CDK4 gain of function mutations complement PTEN loss to drive prostate cancer
initiation and drug resistance, respectively. In my first aim, I will test the necessity and sufficiency of IRS4
gain of function to drive tumor initiation through MAPK activation and downstream transcriptional alterations. For
my second aim, I will test the necessity and sufficiency of CDK4 gain of function to drive drug resistance through
cell cycle dysregulation and investigate the reversibility of this phenotype in patient-derived organoids. My
sponsor Rohit Bose, MD, PhD, has extensive experience in genetic and transcriptional network alterations
underlying prostate tumor initiation. My co-sponsor Kevin Shannon, MD, has renowned experience studying
MAPK circuitry and drug resistance in cancer. Additionally, I have secured scientific support and career
mentorship from a respected and prolific cadre of investigators with complementary expertise, Dr. Felix Feng
(prostate cancer genomics), Dr. Rahul Aggarwal (drug-resistant tumor samples), Dr. Catherine Smith (cell cycle
dysregulation and tumor evolution), Dr. Franklin Huang (prostate cancer genomics and health disparities), and
Dr. Hani Goodarzi (multi-omics and tumor evolution). Concurrently, I will continue bimonthly clinical
preceptorships with Drs. Aggarwal, Bose, and Feng at the UCSF Helen Diller Family Comprehensive Cancer
Center. Overall, the proposed work will further our understanding of tumor initiation and drug resistance in
prostate cancer, laying the groundwork for improved detection and treatment. Moreover, this fellowship will foster
my training in cancer biology and geneti...

## Key facts

- **NIH application ID:** 10929934
- **Project number:** 5F31CA278406-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Matthew James Ryan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $11,333
- **Award type:** 5
- **Project period:** 2023-09-01 → 2024-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929934

## Citation

> US National Institutes of Health, RePORTER application 10929934, Dissecting Early Tumor Evolution to Uncover Mechanisms of Tumor Initiation and Drug Resistance (5F31CA278406-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10929934. Licensed CC0.

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