# Preclinical analyses of advanced prostate cancer in genetically-engineered mice

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $546,963

## Abstract

Project Summary/Abstract
 Advanced prostate cancer represents a major cause of cancer death in men, usually as a consequence
of treatment failure, which gives rise to aggressive disease variants that are highly metastatic. Among the major
biological processes that are causally dysregulated in advanced prostate cancer are those related to DNA repair.
Notably, BRCA1 and BRCA2, are among the most frequently altered DNA repair genes in advanced prostate
cancer, and are also key targets for its treatment. To study their functions in prostate cancer, we have generated
genetically-engineered mouse models (GEMMs) based on inducible loss-of-function of Brca1 and Brca2 in the
prostate. In preliminary studies, we have found that loss-of-function of Brca2 results in aggressive prostate
tumors with highly penetrant metastases, including to bone, that are coincident with increased DNA damage and
accelerated by androgen deprivation. In parallel, we have developed computational tools to elucidate the
molecular determinants of Brca1 and Brca2 functions in prostate cancer. We have also developed a new
precision oncology platform called OncoLoop, to computationally match individual patients to individual GEMMs,
and to predict and validate drugs that target specific patient-GEMM pairs.
 Leveraging these models and resources, we will systematically investigate the functions of BRCA1 and
BRCA2 in prostate cancer, guided by the hypothesis that defective DNA repair plays an important role in
prostate cancer progression and treatment, particularly in the context of androgen deprivation. In Aim 1, we will
investigate the consequences of loss-of-function of Brca1 and Brca2 in GEMMs, GEMM-derived organoid
models, and patient-derived human organoid models for prostate tumorigenesis, metastasis, and DNA damage
response. These studies will provide fundamental insights into the functions of BRCA1 and BRCA2 in prostate
cancer and elucidate the relationship of DNA repair mechanisms for disease progression. In Aim 2, we will
investigate molecular determinants of DNA repair functions in prostate cancer by identifying and functionally
characterizing master regulators (MRs) that represent mechanistic determinants of Brca1 and Brca2 loss-of-
function in prostate tumors and metastases. MRs will be prioritized based on conservation with human prostate
cancer, and functionally validated in mouse and human organoids. We will complement these studies by
analyses of tumors and metastases using single-nuclei RNA-sequencing (snRNA-seq) to identify MR signatures
associated with specific cell states. In Aim 3, we will leverage our GEMMs, GEMM-derived organoids and
allografts, and patient-derived organotypic models to pursue co-clinical investigations of DNA repair function in
prostate cancer. In Aim 3A, we will systematically evaluate drugs/drug combinations currently in or advancing
to clinical practice. In Aim 3B, we will use the OncoLoop platform to predict new drugs that target DNA repair i...

## Key facts

- **NIH application ID:** 10792933
- **Project number:** 5R01CA173481-12
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Cory Abate-Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,963
- **Award type:** 5
- **Project period:** 2013-08-06 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792933

## Citation

> US National Institutes of Health, RePORTER application 10792933, Preclinical analyses of advanced prostate cancer in genetically-engineered mice (5R01CA173481-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10792933. Licensed CC0.

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