Determining the Role of CDK12 in Driving Prostate Cancer Initiation, Progression, and Responses to Therapeutics
Abstract
Background: It s estimated that more than 29,000 men will die from metastatic prostate cancer in the United States in 2018. Recent research effort determined that there are multiple genetic types of human prostate cancer and, because of that, they need different therapeutic interventions. For example, a significant proportion of metastatic prostate cancers have inactivation of specific DNA repair pathways. This contributed to cancer development in the first place. However, this deficiency also made these tumors highly sensitive to DNA damage. Drugs that damage DNA or inhibit the work of the DNA repair pathways that are still working in such tumors prove to be very efficient for the treatment of these types of cancers. This is because the normal cells can use multiple DNA repair pathways, but tumors have no DNA repair pathways left after those few that were still functioning are now inhibited by drugs or overwhelmed by massive DNA damage. Approximately half of metastatic prostate cancers are positive for the ETS fusion gene. In addition, up to 7% of ETS-negative metastatic prostate cancers have inactivation of a gene called CDK12. This gene is known to be important for proper DNA repair; however, exactly how it works in general and in prostate cancer specifically is not clear. We believe that ETS-positive prostate cancers are hypersensitive to drugs inhibiting CDK12. We also believe that CDK12-mutant prostate cancers are hypersensitive to DNA-damaging drugs, inhibitors of DNA repair, and immunotherapy. This will be investigated in our proposed study. Hypotheses/Objectives: We hypothesize that inactivation of CDK12 causes prostate cancer development, but also makes these tumors sensitive to the treatment by DNA-damaging drugs, inhibitors of DNA repair, and immunotherapeutic interventions. We also hypothesize that ETS-positive prostate cancers are hypersensitive to CDK12 inhibition. The Specific Aims of the project will (1) determine whether inactivation of Cdk12 results in prostate cancer development or contributes to prostate cancer progression; (2) determine whether Cdk12-deficient tumors are especially sensitive to carboplatin or drugs that inhibit DNA repair and whether ETS-positive prostate cancer is sensitive to CDK12 inhibition; and (3) determine whether Cdk12-deficient tumors can be efficiently targeted by immunotherapy. In many projects, we will use mouse models of prostate cancer. This will tremendously improve the physiological relevance of this study because we will study prostate cancer as it is developing in its proper microenvironment in highly controlled conditions, growing in a live organism with a normally functioning immune system. The most important findings on prostate tumor drug sensitivity and vulnerabilities will be confirmed using human prostate cancer cells growing in tissue culture and in immunocompromised mice. Impact: This proposal directly addresses a 2018 PCRP Overarching Challenge. It aims (1) to develop a better understanding of CDK12-mutant PCa to define the biology of lethal prostate cancer and (2) to test the vulnerability of CDK12-mutant cells to various genome maintenance inhibitors and the vulnerability of ERG-positive prostate cancer to CDK12 inhibition to develop treatments that improve outcomes for men with lethal prostate cancer. Novel aspects of the proposal include the novel research direction involving development of an in vivo mouse model of Cdk12 deficiency, which is supported by preliminary data demonstrating generation of prostate-specific Cdk12 cKO mice. To decrease lethality from prostate cancer, there is a critical need to understand the role and mechanisms of CDK12 in PC and reveal specific vulnerabilities of CDK12-null tumor cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910211
Entities
People
- Valeri Vasioukhin
Organizations
- Fred Hutchinson Cancer Center
- United States Army