Comprehensive Liquid Biomarker for Predicting Early Resistance to Androgen Receptor Signaling Inhibitors in Metastatic 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. 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. The ESP technology is 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. ESP was developed by Dr. Lang and his team at the University of Wisconsin. We will leverage this and other technologies to analyze DNA, RNA, and epigenetic changes in tumor cells. In this proposal, we will determine the extent to which these changes occur in prostate cancer and whether this can be detected in blood samples using a comprehensive technology platform developed by Dr. Lang, Dr. Haffner, and Dr. Zhao. This proposal represents true synergy because neither investigator would be able to move forward on this project without the other’s 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 comprehensive molecular analysis of liquid biopsies. 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 helping us to understand how prostate cancer develops and spreads despite numerous anti-cancer therapies that have been developed over the last decade. This work will also provide a new group of tests to identify patients at risk for treatment resistance. Finally, we will be able to understand how cancer evolves resistance to ultimately develop new classes of drugs that can target or prevent these changes in men with prostate cancer. Identifying patients that are likely to have resistance would thus 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
- Dec 05, 2021
- Source ID
- W81XWH2110205
Entities
People
- Shuang G. Zhao
Organizations
- United States Army
- University of Wisconsin–Madison