# Systems analysis of aggressive prostate cancer pathology

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2020 · $745,463

## Abstract

Project Summary
Tissue pathology is a manifestation of the genomic aberrations that define cancer (i.e. stage, grade, type). In
prostate cancer, the best prognostic marker is Gleason score, the composite tumor grading system that
summarizes primary tumor morphology. Subsets of patients with localized disease inevitably develop
metastases, a point where it is often too late for curative treatment. Thus, we propose to model and
therapeutically target molecular subtypes that drive aggressive primary prostate cancer. We start from large,
–omic datasets and use tissue pathology and gene expression as the readout of disease development. To
evaluate the direct effect of molecular drivers of aggressive primary disease, we use a novel prostate stem cell,
tissue recombination mouse model that recapitulates prostate development and tissue pathology. To model
specific molecular subtypes, we will genetically engineer mouse prostate stem cells to introduce gene
knockouts or Tet-regulated genes. These engineered cells will then be combined with fetal urogenital
mesenchyme and engrafted under the mouse kidney capsule to produce prostate structures. We will evaluate
tissue pathology and isolate regions of interest with aggressive tissue morphology (e.g., cribriform patterning)
for RNA sequencing. Using this approach to model three mutually exclusive molecular subtypes, we can
directly compare and contrasts gene expression and pathways changes to identify common and subtype-
specific effects. Using these data, along with –omic data from patients, we will use two network-based
computational models to identify novel therapeutic treatments and capture the systems-level gene regulation
and functional relationships. The therapeutic predictions will be screened in vitro using engineered mouse and
human cells with promising treatments being promoted for testing in the tissue recombination mouse model.
Overall, through this project, we will study drivers of aggressive primary prostate cancer, characterize
mechanisms of disease development, and identify pre-clinical pharmacological treatment strategies.
Computational models and the prostate stem cells will be valuable resources for the CSBC and larger research
communities.

## Key facts

- **NIH application ID:** 9999532
- **Project number:** 5U01CA231978-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James Christopher Costello
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $745,463
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999532

## Citation

> US National Institutes of Health, RePORTER application 9999532, Systems analysis of aggressive prostate cancer pathology (5U01CA231978-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999532. Licensed CC0.

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