Epigenetic Analysis of Circulating Tumor Cells
Abstract
Scientific Objective and Rationale: Prostate cancer is the most frequently diagnosed cancer for males in the United States. Normal prostate tissue depends on male sex hormones called androgens, such as testosterone, for healthy function. Prostate cancer tumors retain this androgen-dependent property to survive and grow. Therefore, current therapies for prostate cancers 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 deaths. 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. Changes in DNA that do not involve mutations have been identified as playing a key role in the development of treatment resistance. Known as epigenetic changes, these accumulate in prostate cancer cells and promote aggressive, metastatic prostate cancer. Understanding the epigenetics in prostate cancer is difficult due to the challenges of performing invasive bone biopsies on men when treatment resistance occurs. In this proposal, we develop new technologies and assays to test tumor cells that can be isolated from the blood of patients with prostate cancer without requiring invasive biopsies. 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 cells in circulation can have different fates, with some of them responsible for the development of metastatic prostate cancer. VERSA was co-developed by Drs. Lang and Beebe at the University of Wisconsin to analyze these rare tumor cells. In collaboration with Dr. Michael Haffner, we have isolated DNA from as few as 10 cells and identified epigenetic changes that are found in prostate cancer. In this proposal, the Principal Investigator (PI) will refine this technology to detect epigenetic changes in cells collected from blood using the VERSA platform. Research Goals: The overarching career goal of the PI is to become a translational scientist developing new tests and treatments for men with prostate cancer. This will be her first grant and will serve as a catalyst for her career in prostate cancer. To achieve these goals, she has assembled a team of mentors focused on translational biomedical engineering to develop new tools and technologies for men with prostate cancer. 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 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 2-year grant period, we will have optimized this assay and performed the first testing on blood samples from patients with prostate cancer. This is a key step required before we can implement and test the effectiveness of this blood test in larger-scale trials. Advancing the Field of Prostate Cancer: If successful, the ultimate outcome of this work would (1) advance our understanding of epigenetics in the development of metastatic disease; (2) provide new tests that could help physicians and their patients to predict and monitor responses to treatments; and (3) facilitate discovery of new
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710096
Entities
People
- Tamara Rodems
Organizations
- United States Army
- University of Wisconsin–Madison