Defining Epigenetic Drivers of Treatment Resistance in Metastatic Prostate Cancer
Abstract
The Problem of Drug Resistance in Advanced Disease: Metastatic castration-resistant prostate cancer (mCRPC) is the second leading cause of cancer-related deaths in men in the USA. Although prostate tumors respond initially to androgen deprivation therapy (ADT), many patients develop resistance to ADT, progress to more advanced disease stages, and respond only temporarily to second-line androgen-targeted therapies. Treatment resistance can develop when cancers acquire new mutations or genetic alterations that confer new biological properties which enable the cancers to avoid being killed by available therapies. Identification of Epigenomic Drivers of ADT Resistance: The most common approach for identifying drivers of drug resistance in cancer is through sequencing tumor DNA, which can reveal mutations that arise after therapy. However, it is now clear that many patients develop resistance to androgen targeted therapies without acquiring new mutations that can be detected this way. Epigenomic alterations are chemical modifications of DNA that change gene activity without creating mutations detected through traditional sequencing. Our group has reported evidence that epigenomic changes to tumor DNA are associated with aggressive disease. Thus, a crucial unanswered question is, Which epigenomic alterations trigger resistance to androgen-targeted therapies? Barriers to Studying Treatment Resistance in mCRPC Patients: A major barrier to studying drug resistance in mCRPC patients is the lack of availability of tumor and blood samples taken from the same patient both before the initiation of treatment and after the development of resistance. Over the last decade, our team has assembled the largest collection in the world (to our knowledge) of matched mCRPC biopsies before treatment and after resistance to advanced ADT therapies (abiraterone or enzalutamide). This valuable tissue repository will allow us to study both genetic and epigenomic alterations associated with treatment resistance. Rationale of the Study: Our group has now optimized comprehensive genomic and epigenomic sequencing approaches, and has used these techniques to profile over 100 metastases from mCRPC patients (Quigley et al, Cell 2018; Zhao et al, Nature Genetics 2020). We have also gathered circulating tumor DNA (from blood samples) from these same mCRPC patients. Our sequencing studies have resulted in the identification of new alterations affecting genes critical to prostate cancer progression (such as the androgen receptor), as well as the discovery of new molecular subtypes of mCRPC (such as a subtype characterized by much more methylation, a specific epigenomic alteration, than most mCRPC samples). We now propose to apply these optimized sequencing approaches to our unique cohort of matched biopsy and blood samples, obtained from the same patients before initiation of abiraterone or enzalutamide, and also at the time of the development of resistance. The goals of our grant are: 1. To identify novel mechanisms of resistance to second-line androgen-targeted therapy 2. To use liquid biopsies to characterize epigenomic resistance mechanisms within the patient Clinical Applicability of the Proposed Research: Understanding the mechanism by which metastatic disease develops resistance to androgen-targeted therapy is essential to developing drugs that overcome resistance. Establishing the mechanism of resistance and developing liquid biopsy techniques to investigate these mechanisms without invasive solid tissue biopsies may aid clinical decision-making by identifying patients with aggressive forms of PCa that may need treatment intensification. The long-term goal of this project is to translate our scientific findings into clinical treatments and predictive tools. We believe that the contributions made from this project will be clinically significant and will eventually benefit patients with aggressive metastatic disease ref
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210833
Entities
People
- Felix Y. Feng
Organizations
- United States Army
- University of California, San Francisco