Androgen Receptor Gene Rearrangements in EpCAM-Positive and -Negative Circulating Tumor Cells: Biomarkers for Castrate-Resistant Prostate Cancer
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, newer drugs that interfere more effectively with androgen production or action have been developed that can extend the life of men with castration-resistant prostate cancer for an additional 4-6 months, but resistance to these new drugs remains a major problem. We have developed complementary technologies in our labs 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. These tumor cell cells in circulation can be very heterogeneous with some of them responsible for the development of metastatic prostate cancer. VERSA was developed by Dr. Lang and his team at the University of Wisconsin to analyze these rare tumor cells. The other technologies that we will leverage are methods to analyze the AR gene in genetic extracts from tumor cells. AR gene analysis has been shown to identify alterations that can cause resistance to therapy. These AR gene analysis technologies were developed by Dr. Dehm and his team at the University of Minnesota. In this proposal, we will test whether the AR gene alterations identified by Dr. Dehm 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, and 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 AR gene in tumor cells from blood. This is a key step 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 androgen production or action. Identifying patients that are likely to have resistance to androgen-targeting drugs would enable physicians to try out alternative therapies that may have a more beneficial effect.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510500
Entities
People
- Joshua M. Lang
Organizations
- United States Army
- University of Wisconsin–Madison