# Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $269,895

## Abstract

With the wide-spread integration of next-generation sequencing technology over the past several years,
comprehensive genomic studies have shown that prostate cancers can be classified into different molecular
subtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity to
design rational precision oncology approaches for treatment. To this end, we have recently identified and
characterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shown
that it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostate
cancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes, including homologous
recombination and mismatch repair-deficient, that is associated with a focal tandem duplication (FTD)
phenotype. Importantly, CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions, and
this is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment.
Accordingly, preliminary results from mCRPC patients in our cohort suggest that they may have a higher
likelihood of response to immune checkpoint blockade. We, therefore, hypothesize that inactivation of CDK12
results in an immunogenic class of mCRPC that may benefit from immune-directed therapies. This hypothesis
will be explored through the following Specific Aims:
Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethal
targets. Experiments in this Aim will focus on in vitro methods, bioinformatics analyses, and a CRISPR screen
to examine how CDK12 loss impacts prostate cancer pathogenesis and drives the emergence of an
immunogenomic phenotype.
Aim 2: Determine the impact of Cdk12 ablation on prostate tumor growth and immune response in vivo. We will
generate several Cdk12-null mouse prostate models to directly evaluate the role of Cdk12 in prostate
tumorigenesis and response to immune checkpoint blockade.
Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade for
CDK12-mutant mCPRC patients. Using samples from our Phase II trial (IMPACT) of nivolumab and ipilimumab
in CDK12-mutant patients, we will analyze changes in the immune response and determine tumor-intrinsic
biomarkers of response.
Together, completion of these Aims will define the role of CDK12 in prostate tumorigenesis and assess precision
oncology approaches for this recently identified subtype of prostate cancer.

## Key facts

- **NIH application ID:** 10006872
- **Project number:** 5P50CA186786-07
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ARUL M CHINNAIYAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $269,895
- **Award type:** 5
- **Project period:** 2014-09-11 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006872

## Citation

> US National Institutes of Health, RePORTER application 10006872, Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12 (5P50CA186786-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10006872. Licensed CC0.

---

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