Defining Clinically Actionable Subtypes of Castration-Resistant Prostate Cancer Through Epigenetic Cell-Free DNA Analysis
Abstract
Metastatic prostate cancer (mPC) – the term for when the cancer has spread beyond the prostate – is not curable and is the form of the disease that men die from. The backbone of treatment for mPC includes medications that block the actions of androgens (male sex hormones), such as testosterone. Unfortunately, all men with mPC eventually stop responding to anti-androgen therapy and become castration-resistant. Fortunately, several new drugs significantly prolong survival for men with castration-resistant mPC. Further reducing morbidity (injury and suffering) and mortality (death) for men with mPC is contingent upon addressing two barriers. First, we lack the tools to predict how well an individual man will respond to specific drugs. The ability to do so would facilitate prioritizing the most effective treatments over those that may cause significant side effects with little to no benefit. Second, despite numerous effective therapies for men with mPC cancer, tumors eventually become resistant to all available treatments and men succumb to their illness. Developing tools to personalize therapeutic decision-making for individual men and understanding how tumors become resistant to current treatments so that we can develop new effective drugs are critical to prolonging survival for men with mPC. Efforts to understand how mPC develops treatment resistance have largely focused on genetics, i.e., studying changes to the sequence of the DNA in important PC genes. It has become increasingly clear that changes in epigenetics also drive PC resistance. Epigenetics refers to the DNA modifications that cells use to turn genes on or off. Differences in epigenetics explain why, despite having the same DNA, a skin cell looks and functions differently from a muscle cell – or a PC cell is sensitive or resistant to one drug or another. Several challenges have prohibited major advances into our understanding of the role of epigenetics in contributing to response and resistance to treatments in mPC. First, traditional tools for epigenetic analysis require larger amounts of tissue than is often feasible to obtain from a mPC tumor biopsy. Second, there are no large datasets of paired tumor biopsies from the same patient collected before treatment and at the time of progression (i.e., when the treatment is no longer working). The ability to detect cancer from a blood draw or urine sounds like science fiction. However, it is now possible to analyze DNA that is shed from tumor cells into the bloodstream. So-called liquid biopsies offer several advantages over conventional tumor tissue biopsies: (1) they can be performed as part of a routine blood collection; (2) they are less invasive and pose less risk to patients; and (3) they can be performed at multiple timepoints. Until recently, tools to perform epigenetic tumor analysis using liquid biopsies were lacking. To overcome this barrier, we have developed several innovative tools to study the epigenetics of mPC by analyzing tumor DNA circulating in the bloodstream. Our objective is to utilize these exciting new tools for blood-based analysis of tumor epigenetics to develop liquid biopsy tests to optimize treatment decision-making for men with mPC and generate novel insights into epigenetic factors that drive treatment resistance. In Aim 1, we will develop a liquid biopsy test to detect epigenetic subtypes of mPC that, when identified, provide additional treatment options for patients. In Aim 2, we will develop a liquid biopsy test to identify men most and least likely to benefit from Abiraterone and Enzalutamide (the two most frequently used drugs in mPC) and determine how tumors change their epigenetic landscape to become resistant to these drugs. Aim 3 has a similar goal to Aim 2, but focuses on Lutetium-PSMA, the most recent life-prolonging drug to be approved for men with mPC. These aims will make substantial contributions towards defining the biology of and deve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310048
Entities
People
- Jacob E Berchuck
Organizations
- Dana–Farber Cancer Institute
- United States Army