Defining and Targeting the DNA Hypomethylation Phenotype in Advanced Prostate Cancer
Abstract
All cells in the human body have the same DNA sequence, but a cell in the heart looks and functions very differently than a cell in the prostate. These differences are dictated by an additional layer of information that is encoded by modifications of the DNA molecule that do not change the DNA sequence. Such epi-genetic marks (literally meaning on top of the genome) define the function and behavior of all cells. Of the many epigenetics marks that are currently known, DNA methylation, which involves the addition of a chemical group directly on the DNA molecule, is the best studied. DNA methylation is essential for cellular differentiation and determines the fate of a cell. Although essential for every cell in the human body, cancers find unique ways to highjack and change these epigenetics marks. Prostate cancers in particular show major DNA methylation changes. We therefore reasoned that, by understanding the pattern of DNA methylation changes in prostate cancer, we can identify unique vulnerabilities that would allow us to treat prostate cancers more effectively. These studies led us to unmask a novel type of prostate cancer that is characterized by highly distinct DNA methylation changes. Whereas the DNA of normal cells and most prostate cancers is peppered with methylation marks, this type of prostate cancer shows a dramatic loss of DNA methylation. This new subclass of prostate cancer makes up around 10-15% of advanced tumors. Further, these tumors show a more aggressive behavior. However, we hypothesize that the loss of DNA methylation likely generates unique vulnerabilities in these cancer cells that we can target with specific therapies. We are therefore determined to identify the “Achilles’ Heel” of these epigenetically unique tumors. To this end, we will take a very close look at these newly discovered DNA Hypomethylated Prostate Cancers (DHMPCs). We will first study the relationship between DNA methylation changes and the clinical presentation in over 2,500 prostate cancers. Next, we will comprehensively determine the molecular makeup of these tumors to look for unique vulnerabilities. We will apply novel DNA sequencing technologies to decipher how exactly these tumors can bypass the need for DNA methylation and why they show an aggressive behavior. To do this, we will leverage new model systems that we have developed in our laboratory. The ultimate goal of this research is to develop new and innovative therapies that allow us to specifically target this unique subset of prostate cancers. To this end, we will perform cutting-edge genetic tests and drug screens that will allow us to unmask vulnerabilities in DHMPCs, and we will test these drugs in pre-clinical intervention trials using patient-derived models. Prostate cancer is a devastating disease without a one-size-fits-all treatment. There is a great need for identifying distinct subtypes of prostate cancer and developing highly specific therapies to target each subtype. Here we aim to characterize a new epigenetically defined subtype of prostate cancer. We will use comprehensive molecular approaches to define vulnerabilities in these tumors and identify drugs that are highly effective for hypomethylated tumors. This work could ultimately lead to a more precise molecular definition of prostate cancers and novel therapies that target unique weaknesses in each type of prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110229
Entities
People
- Michael C. Haffner
Organizations
- Fred Hutchinson Cancer Center
- United States Army