Developing a cell-free methylated DNA-based biomarker to detect neuroendocrine prostate cancer
Abstract
Objective and Rationale: Prostate cancer (PC) is the second most common cause of cancer death among men in the United States. Metastatic PC – the stage when cancer spreads beyond the prostate – shortens life expectancy and is not curable. Treatment for metastatic PC involves medications that block the actions of androgens (male sex hormones, such as testosterone). Unfortunately, men with metastatic PC eventually stop responding to anti-androgen therapy and become “castration-resistant.” Potent anti-androgen drugs, such as abiraterone and enzalutamide, prolong survival for men with castration-resistant disease, yet responses are limited and disease progression is nearly universal. Understanding how tumors develop resistance to antiandrogen therapy is critical to developing new treatments that will reduce death from PC. Cancer cells commonly become resistant to anti-androgen therapy by transforming from prostate adenocarcinoma (PRAD), the general cell type in PC, into a different cell type called neuroendocrine prostate cancer (NEPC). NEPC cells look and behave differently from PRAD cells in important ways: they are more aggressive, are associated with poor response to anti-androgen therapy, and are associated with shorter survival. Improving outcomes for men diagnosed with NEPC requires two discoveries: (1) developing the ability to detect NEPC early in the natural history of the disease and (2) identifying new therapies that prolong survival for men with NEPC. Investigating differences in the epigenetics of PRAD and NEPC tumors will address these critical and unmet needs. Epigenetics refers to the DNA modifications that cells use to turn genes on or off. Differences in epigenetics explain why a skin cell looks different from a muscle cell, despite having the same DNA. Cells control DNA by adding methyl groups, which serve as epigenetic “stop signs” to turn genes off, and removing DNA methylation to turns genes on. Like skin and muscles cells, PRAD and NEPC tumors have different methylation patterns. In Aim 1, we will use an innovative technique – cfMeDIP-seq (cell-free methylated DNA immunoprecipitation and high throughput sequencing) – to detect NEPC-specific DNA methylation in blood samples. (The conventional approach for diagnosing NEPC requires an invasive biopsy to obtain tumor tissue.) We will use cfMeDIP-seq to identify DNA methylation sites that distinguish NEPC from PRAD and explore using NEPC-specific sites to accurately predict who in an independent group of patients does and does not have NEPC. In Aim 2, we will use a cutting-edge technique, scATAC-seq (single cell assay for transposase-accessible chromatin using sequencing), to visualize epigenetic profiles of individual tumor cells. We will utilize scATAC-seq to identify cells that are in the process of transforming from PRAD to NEPC and identify genes that are driving this process. We will then use a novel DNA-editing technology termed “CRISPR/Cas9” to investigate which of these genes are critical to the transformation process and promising new drug targets for preventing this lethal PC disease variant. Applicability of Research: Two of the Prostate Cancer Research Program’s Overarching Challenges are addressed in this proposal: (1) developing treatments that improve outcomes for men with lethal prostate cancer and (2) defining the biology of lethal prostate cancer to reduce death. Specifically, this project has two potential clinical applications for men with advanced PC: (1) development of a non-invasive, blood-based test to accurately detect NEPC in men with castration-resistant PC and (2) identification of novel therapeutic targets to overcome NEPC as a mechanism of drug resistance. Translating this work to prolong survival for men with advanced PC could occur rapidly (1-2 years) for the diagnostic biomarker, while drug development would likely take 5-10 years. These experiments will nominate potential new drug targets for tre
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010118
Entities
People
- Jacob E Berchuck
Organizations
- Dana–Farber Cancer Institute
- United States Army