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.

Public Health Relevance

Large-scale genomic studies have shown that metastatic castration-resistant prostate cancer (mCRPC) is comprised of several molecular subtypes that can be targeted through rational precision oncology approaches. We recently identified a novel subtype of prostate cancer enriched in metastatic disease that is typified by biallelic inactivation of CDK12 which leads to genomic instability, increased neoantigen burden, and an active immune response. In this proposal, we will explore this newly defined immunogenic subtype of mCRPC at the mechanistic level and also, for the first time, evaluate targeted therapeutics for CDK12-mutant mCRPC patients, focusing on immune checkpoint blockade agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA186786-07
Application #
10006872
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2014-09-11
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cie?lik, Marcin et al. (2018) Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. Nat Genet 50:814-824
Hussain, Maha; Daignault-Newton, Stephanie; Twardowski, Przemyslaw W et al. (2018) Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol 36:991-999
Salami, Simpa S; Hovelson, Daniel H; Kaplan, Jeremy B et al. (2018) Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3:
Zhao, Shanshan; Leonardson, Amy; Geybels, Milan S et al. (2018) A five-CpG DNA methylation score to predict metastatic-lethal outcomes in men treated with radical prostatectomy for localized prostate cancer. Prostate :
Niknafs, Yashar S; Pandian, Balaji; Gajjar, Tilak et al. (2018) MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data. Neoplasia 20:1144-1149
Xiao, Lanbo; Tien, Jean C; Vo, Josh et al. (2018) Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer. Cancer Res 78:5731-5740
Piert, Morand; Shankar, Prasad R; Montgomery, Jeffrey et al. (2018) Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications. EJNMMI Res 8:23
Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14
Rice, John D; Tsodikov, Alex (2017) Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random-threshold damage-resistance model. Stat Med 36:1924-1935
Shen, Rex; Luo, Lan; Jiang, Hui (2017) Identification of gene pairs through penalized regression subject to constraints. BMC Bioinformatics 18:466

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