Understanding the Role of CDK12 and Identifying Immunotherapy and Synthetic Lethal Targeting Strategies
Abstract
Metastatic castrate-resistant prostate cancer is an incurable and invariably fatal disease. The National Cancer Institute estimates that nearly 30,000 men will die from prostate cancer in the United States this year. Currently approved therapies for metastatic castrate-resistant prostate cancer extend survival by only a few months and are administered sequentially, irrespective of the mutations within each individual patient’s tumor. As we learn more about the drivers of prostate cancer, we are discovering that certain molecular alterations can be specifically targeted. This paradigm of “precision oncology” treatments – where patients’ mutations are matched to a specific targeted therapy – is one of the main goals of modern cancer therapy. We and others recently identified recurrent, biallelic loss-of-function mutations in a gene called cyclin-dependent kinase 12 (CDK12) in men with advanced prostate cancer. Interestingly, the genomes of CDK12-mutated tumors display a distinct signature of genomic instability, characterized by tandem duplications. However, the mechanisms underlying this phenomenon and the potential therapeutic implications remain largely unexplored. Moreover, CDK12 mutations define a subclass of prostate cancer with aggressive clinical behaviors, including a shorter time to metastasis and castration-resistant disease. Therefore, identifying the role of CDK12 and new treatment strategies to combat this deadly subtype of metastatic prostate cancer is critical. I hypothesize that CDK12 regulates DNA damage repair and DNA replication pathways to protect genome integrity and that loss of CDK12 generates a pro-inflammatory signature that alters the tumor immune microenvironment to increase susceptibility to immune checkpoint inhibitors. Finally, I hypothesize that genetic CRISPR screens and chemical small molecule screens will yield new therapeutic strategies to attack CDK12-mutated prostate cancer. My project will capitalize on several unique sets of isogenic CDK12-deficient cell lines that I have generated through CRISPR/Cas9 genomic editing technology in order to understand the biology of CDK12 and the consequences of losing CDK12 in prostate cancer cells. In Aim 1, I will investigate how CDK12 regulates genome stability, the DNA replication fork, and tandem duplication formation. In Aim 2, I will analyze how CDK12 loss affects the immune system and test responses to various immunotherapy drugs in CDK12-deficient prostate cancer. In Aim 3, I will identify new ways of targeting CDK12-deficient prostate cancer by performing a genome-wide inhibition screen to find new ways of killing CDK12-deficient cells. In addition, I will conduct chemical screens to identify drugs and drug combinations that specifically target CDK12-deficient cells. As a physician-scientist, I take care of patients with advanced prostate cancer and conduct translational prostate cancer research that I hope will improve the lives of my patients. I have a strong background and experience in oncology and cancer biology and am fully committed to a career as an academic, laboratory-based investigator. The Physician Research Award will help me gain the additional expertise in CRISPR-based synthetic lethal screens, small molecule screens, and tumor immunology to successfully lead my own research team. My mentors, Dr. Felix Feng and Dr. Alan Ashworth, have outstanding track records in mentoring physician scientists and have expertise that is complementary to my own to help me achieve my goals. This work will be the first to characterize the function of CDK12 and identify immunotherapy and synthetic lethal targeting strategies for this molecular subtype of prostate cancer. This project also has broad applicability to advance our understanding of CDK12 in prostate cancer. Since CDK12 can be inhibited by specific drugs, findings from this project may also impact patients without CDK12 mutations. The goals of this project a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010136
Entities
People
- Jonathan Chou
Organizations
- United States Army
- University of California, San Francisco