Investigating the Genomic Evolution of Metastatic Castration-Resistant 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 United States. 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 that enable the cancers to avoid being killed by available therapies. The Identification of Genetic Drivers of ADT Resistance: The most common approach for identifying genetic drivers of drug resistance in cancer is through genomic sequencing, which can reveal new mutations or genetic alterations that have arisen after therapy. However, to date, the vast majority of genomic studies of mCRPC have focused on genes that encode a protein, and it is notable that these genes (called the tumor exome) only comprise 1.5 percent of the entire tumor genome. Thus, crucial unanswered questions are: What about the other 98.5% of the genome? Which genes in this 98.5% majority (termed non-coding genes) trigger resistance to ADT? Rationale of the Study: To comprehensively investigate the landscape of genomic alterations in mCRPC, we recently performed deep whole genome sequencing (which assesses 100% of the genome) of tumor metastases from 101 patients with mCRPC. Our analysis identified a novel alteration present in 80% of patients that drives the expression of the androgen receptor (a known driver of prostate cancer) and thereby promotes ADT resistance. This alteration is exclusively found in tumors with resistance to primary ADT. Importantly, this alteration occurs at a location in the genome that does not code for a gene and had been overlooked in previous studies of prostate cancer that focused exclusively on the coding genome (i.e., the tumor exome). The observation that a novel resistance mechanism could only be discovered through whole genome sequencing motivated us to directly compare the paired whole genomes of mCRPC patients before and after they developed second line androgen-targeted therapy resistance. We have previously studied how mCRPC develops resistance to a drug that inhibits the activity of a protein called PARP1. These studies employed DNA analysis on liquid biopsies, analyzing small fragments of tumor DNA that circulate temporarily in a patients bloodstream after tumor cells die and burst open. A key observation from this study was that distinct tumor cells developed therapeutic response in a multitude of ways within a single patient, and that liquid biopsies are an effective way to characterize the ensemble of resistance mechanisms. Applications of liquid biopsies have so far been restricted to interrogating small sections of the genome. In our preliminary data, we demonstrate that analysis of whole tumor genomes by liquid biopsy can identify genetic and structural alterations in the tumor DNA, making it possible for the first time to identify all tumor mutations and structural alterations from a blood draw. 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 identify the different resistance mechanisms that exist within individual patients. 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 prostate cancer that may need treatment intensification. The long-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910682
Entities
People
- Felix Y. Feng
Organizations
- United States Army
- University of California, San Francisco