Blood-Based Epigenomic Correlates of Aggressive Prostate Cancer Phenotypes
Abstract
Our blood contains DNA that is released from cells throughout the body as they die. Blood from patients with prostate cancer often contains DNA that came from dying prostate cancer cells, known as circulating tumor DNA (ctDNA). Studying ctDNA to better understand and treat cancer has generated great interest in the past decade. Analyzing DNA from blood can potentially provide important information about a cancer without requiring a patient to undergo a procedure to biopsy the cancer. Researchers have studied the sequence of ctDNA to find mutations (changes in the normal DNA sequence) that drive cancer or allow it to stop responding to treatments. However, many of the properties that distinguish cancer cells from normal cells are not due to mutations in the DNA sequence, meaning they cannot be studied by simply sequencing ctDNA. Rather, many properties that distinguish cancer cells are epigenetic, meaning they have to do with how portions of DNA are turned on or off rather than the sequence of DNA. This proposal takes advantage of a promising new technology developed in Dr. Matthew Freedman’s laboratory for studying epigenetic changes in ctDNA. With only a blood draw, this technology, called “nucleoscan,” can identify epigenetic changes in prostate cancer cells from ctDNA. Because epigenetic changes are thought to be responsible for the aggressive behavior of lethal prostate cancer, nucleoscan is a promising tool to understand what drives this disease and find new ways to treat it. The proposed project will take advantage of a large collection of tumor and blood samples that have been donated by prostate cancer patients at the Dana-Farber Cancer Institute over the last two decades. We will perform nucleoscan to study epigenetic changes in cancer from these blood cells. We will address three areas where there is a clinical unmet need or knowledge gap that limits our ability to care for men with prostate cancer: (1) We will study the epigenetic changes that allow prostate cancers to stop responding to treatments. (2) We will study how certain prostate cancers transform into a very aggressive subtype, called “neuroendocrine prostate cancer.” over time. (3) We will use nucleoscan to identify cancers that are unable to properly repair breaks in their DNA and may therefore respond well to specific medications called PARP inhibitors. This project will benefit Veterans with advanced prostate cancer by helping to “define the biology of lethal prostate cancer to reduce death,” addressing an Overarching Challenge of the FY20 PCRP. By studying the epigenetic changes that drive aggressive prostate cancer, we aim to deepen the understanding of what makes some prostate cancers behave aggressively and stop responding to treatments. This knowledge will be critical for developing new treatments for prostate cancer that block or exploit these epigenetic changes. In addition, by using nucleoscan to identify cancers that cannot properly repair DNA damage, it may be possible to determine whether a patient will respond well to existing treatments using only a blood test. Insights gained here would allow doctors to match the right treatment to the right patient and identify and test new treatments. Findings from this research could impact patient care within the next few years. Researcher Development Plan: Sylvan Baca, M.D., Ph.D., will conduct the research under the mentorship of Drs. Mary-Ellen Taplin and Matthew Freedman. Dr. Baca is a young investigator with training in genitourinary oncology and functional epigenomics who is launching a career as an independent prostate cancer researcher. Dr. Taplin is a renowned clinical expert in prostate cancer. Dr. Freedman is a laboratory-based investigator who has pioneered epigenomic profiling of human specimens to study cancer. With his mentors, Dr. Baca has formulated a rigorous plan for structured mentoring, coursework, seminar attendance, and presentation of this work
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110358
Entities
People
- Sylvan C. Baca
Organizations
- Dana–Farber Cancer Institute
- United States Army