Single Cell Heterogeneity of BRCA Reversion Mutations in CRPC
Abstract
Scientific Objective and Rationale: Prostate cancer is the most frequently diagnosed male cancer in the United States. For healthy function, normal prostate tissue depends on androgens, which are male sex hormones such as testosterone. If and when prostate cancer develops in men, tumors retain this androgen-dependent property. Therefore, current therapies for prostate cancer that cannot be managed by surgery and/or radiation include (1) blockade of androgen action with drugs and/or (2) prevention of androgen production through castration. These therapies successfully stop further growth of the cancer and often result in reduced tumor size. However, within an average of 2-3 years, these tumors adapt and develop the ability to start growing again in the low androgen environment created by these treatments. This stage of the disease, termed castration-resistant prostate cancer, is responsible for virtually all prostate cancer death. Recently, new genetic tests have found that approximately 20% of patients with metastatic castration-resistant prostate cancer (mCRPC) bear tumors with mutations in genes, including BRCA2, that control how tumor cells repair damaged DNA. New drugs have been developed that target tumors with these specific mutations. However, prostate cancers can develop new mutations that render these treatments ineffective. We have developed complementary technologies in our laboratories that we think can be leveraged to identify men that are likely to develop this resistance, as well as understand the reasons why resistance has developed. This will move us closer to the goal of achieving more precision in treating patients. One of these technologies is VERSA, a novel method to collect tumor cells from the blood of patients with advanced prostate cancer, as well as extract genetic material from these cells. VERSA was developed by Dr. Lang and his team at the University of Wisconsin. The other technologies that we will leverage are methods to analyze the BRCA gene in genetic extracts from tumor cells. BRCA gene analysis has been shown to identify alterations that can cause resistance to therapy. These BRCA gene analysis technologies were developed by Dr. Feng and his team at the University of California, San Francisco. In this proposal, we will test whether the BRCA gene alterations identified by Dr. Feng can be detected in cells collected from blood using the VERSA platform developed by Dr. Lang. This proposal represents true synergy, because neither investigator would be able to move forward on this project without the other’s technological expertise. Applicability: The outcome of this research has the potential to help all patients who suffer from prostate cancer, especially those who have developed resistance to therapy. This work could lead to the development of a relatively non-invasive testing method involving a simple blood collection that will enable a “liquid biopsy analysis” of the tumor cells. By the end of the 3-year grant period, we will have optimized the procedures necessary to carry out this analysis of the BRCA gene in tumor cells from blood. This is a key step that is required before we can implement and test the effectiveness of this approach in larger-scale trials. Advancing the Field of Prostate Cancer: If successful, the outcome of this work would advance the field by providing a new test for physicians and their patients to predict and monitor responses to treatments that interfere with DNA repair. Identifying patients that are likely to have resistance to these drugs would enable physicians to try out alternative therapies or combinations that may have a more beneficial effect.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910164
Entities
People
- Joshua M. Lang
Organizations
- United States Army
- University of Wisconsin–Madison