Defining and Functionally Characterizing the Epigenome in Lethal Prostate Cancer
Abstract
All cells in the human body contain the same DNA. How is it that a cell in the skin looks different and performs distinct functions than another cell, such as a liver cell? The study of epigenetics addresses this phenomenon. Epigenetics, which literally means “on top of” genetics, determines which genes are turned on or off, independent of alterations in the underlying DNA sequence. The 200 different cell types that compose the human body can be distinguished by the repertoire of genes that are expressed in a given cell type; due to differences in epigenetic signals, a skin cell has a distinct set of genes that are turned “on” compared to a liver cell. Genes are turned “on” by proteins called transcription factors (TFs). TFs bind to certain locations on DNA called regulatory elements. `TFs recognize and bind to specific regulatory elements (i.e., stretches of specific DNA sequences), and this interaction will turn activate or suppress a gene, turning it on or off like a light switch. Recent scientific discoveries have shown that these regulatory elements are essential in cancer biology. Regulatory elements are located throughout the 98% of the human genome that does not code for genes. Until recently, it was difficult to identify, functionally characterize, and therapeutically target these “non-genic” genomic regions due to the lack of tools available for studying the noncoding region. Advances from our (and other) laboratories, however, are enabling the systematic identification and testing of relevant regulatory elements, as well as the ability to target their associated TFs, which were once considered “undruggable.” The ultimate goals of our proposal are to identify and characterize critical regulatory elements that impact progression to metastatic prostate cancer and response to therapy. Aim 1 will characterize, in patient samples, the regulatory DNA landscape as it changes during disease progression. Using a novel state-of-the-art technology, termed genome editing, Aim 2 will identify which regulatory DNA elements are functionally important for mediating resistance to therapy in a well-established cell line model of advanced prostate cancer. Aim 3 will utilize a novel technique to identify key proteins that are bound to the regulatory element. We have assembled a world-class team with the expertise necessary to successfully complete this work. By focusing on epigenetics, our proposal takes a decidedly innovative approach to identifying functionally important regulatory DNA elements and the proteins that bind to them. To date, these DNA regions remain largely understudied compared with the protein coding genome. We strongly believe that each of the aims will provide insights into the DNA regions that are critically important in advanced prostate cancer. Aims 1 and 2 will identify which regulatory DNA elements are important for development of treatment resistance. Aim 3 will identify the proteins that are binding to these DNA elements to drive advanced prostate cancer. Once these critical proteins are clearly identified, the next step upon completion of this project will be to discover novel therapies that block the activity of these proteins in order to turn off the genes they control. When successful, our project will open a completely new area of therapeutic intervention. It is worth noting that the type of work proposed in this grant typically takes place in separate laboratories in an uncoordinated manner, which delays realizing the clinical utility. By contrast, our proposal is deliberately designed to maximize efficiency by coordinating groups with complementary areas of expertise, with the goal of compressing the time it takes from discovery to eventual clinical implementation. More generally, we believe that our approach paves the way for systematically studying cancer and identifying novel therapeutic targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910565
Entities
People
- Matthew L Freedman
Organizations
- Dana–Farber Cancer Institute
- United States Army