Principal Investigators: Dan Robinson, PhD (University of Michigan), Felix Feng, MD (University of California, San Francisco), Ajjai Alva, MD (University of Michigan)

Co-Investigators: Marcin Cieslik, PhD (University of Michigan), Jason Brown, MD (University of Michigan), Jonathan Chou, MD, PhD (University of California, San Francisco), Yi-Mi Wu, PhD (University of Michigan)

Description: 

• Checkpoint immunotherapy is a highly promising type of cancer treatment which has achieved long-term tumor regressions and potentially even cures in some patients with cancers such as melanoma and lung cancer. This type of treatment has not yet been optimized for the treatment of prostate cancer. Identifying prostate cancer patients who are likely to benefit from checkpoint immunotherapy is a critical unmet need.
• Dr. Dan Robinson and team have identified a subtype of prostate cancer that have mutated or deleted both copies of the CDK12 gene. CDK12-mutant prostate cancer have altered molecular features that may cause these tumors to be more easily detected and targeted by anti-cancer immune responses.   Early data from this team suggest that patients with CDK12-mutant prostate cancer may be more likely to respond to checkpoint immunotherapy.
• In this project, Dr. Robinson and team will investigate the genes and molecular features that are altered in CDK12-mutant prostate cancer and determine the mechanisms by which this alteration drives anti-cancer immune responses.
• The team will investigate the mechanisms by which immune responses are generated against CDK12-mutant prostate cancer, including how CDK12 mutations cause other tumor mutations, and which of these alterations is responsible for generating immune responses.
• The team will perform studies to identify genes that are required in CDK12-mutant prostate cancer and may function as therapeutic targets.
• Preclinical models will be studied to validate the efficacy and mechanisms of checkpoint immunotherapy in the treatment of CDK12-mutant prostate cancer.
• Whether combining CDK12 inhibitors with checkpoint immunotherapy may be an effective therapeutic strategy for CDK12-intact prostate cancer will be investigated in preclinical models.
• The team will conduct a phase II clinical trial (IMPACT) testing anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) checkpoint immunotherapy in metastatic prostate cancer patients with CDK12-mutant tumors. The mechanisms of action and determinants of clinical response to checkpoint blockade in CDK12-mutant prostate cancer will be determined using clinical samples from patients in this trial.
• If successful, this team will establish a precision medicine paradigm for the use of checkpoint immunotherapy in prostate cancer.

What this means to patients:  Checkpoint immunotherapy is a highly promising type of cancer treatment, but has yet to be optimized in prostate cancer.Dr. Robinson and team will investigate the efficacy and mechanisms by which checkpoint immunotherapy may work in CDK12-mutant prostate cancer and identify novel immunotherapy treatment strategies for advanced prostate cancer. This will result in the establishment of a precision medicine paradigm for checkpoint immunotherapy in prostate cancer.