Functionally Characterizing the Noncoding Genome of Metastatic Prostate Cancer to Identify Therapeutic Vulnerabilities
Abstract
The human body is composed of billions of cells that are organized into hundreds of different cell types. Interestingly, each cell contains the same DNA sequence, the genetic code that contains the blueprint of life. So how does an identical DNA template encode for every cell type and organ that makes up the human body? The answer is that each type of cell will activate different parts of the DNA, such as a program for “heart” or “lungs,” to enable the development of distinct organs. Similarly, there is a program that drives prostate development and, after this organ is formed, the DNA program is switched off and never used again in normal cells. What we recently discovered is that this “prostate development program” can be abnormally reactivated in prostate cancer. We found that when prostate cancer metastasizes through the body of a patient, it uses this “prostate development program” to enable cancer cells to spread and seed to other organs. This metastatic process is of the highest clinical importance, as practically all patients who succumb to prostate cancer do so from metastatic disease. Consequently, preventing metastatic outgrowth can effectively reduce death due to prostate cancer. But how can we prevent metastatic outgrowth? Based on our recent discovery, we need to find a way to block this “prostate development DNA program” from being activated. This presents a challenge, as this program is composed of over 17,000 individual “DNA switches,” and each of these could be responsible for the metastatic outgrowth. Also, we know that these switches are often mutated in prostate cancer, which can alter their activity and give rise of metastatic disease. Our project therefore is aimed at identifying exactly which of these “DNA switches” and mutations at these sites are important to enable the tumor cell to seed throughout the body and cause lethal metastatic disease. We have formed an international team of expert scientists with complementary areas of expertise to jointly solve this tremendous clinical challenge. First, we will use advanced DNA-activity-technologies to interrogate each of these 17,000 “DNA switches” one by one to determine whether they have the capacity to be active in prostate cancer cells. Second, we will use state-of-the-art DNA editing techniques to suppress each of these “DNA switches” in aggressive prostate cancer cells to identify which ones cause tumor cells to develop resistance to treatment and metastasize. After identifying those specific “switches,” we will validate our findings in several experimental models. Finally, we will determine the effect of DNA mutations on the activity of these “DNA switches” using one of the largest combined DNA sequencing projects of prostate cancer from European- and African-American men. As DNA mutations in prostate cancer vary between patients of different ethnic backgrounds, we have the unique capacity to address a longstanding question of why patients from African-American descent often have a far worse prognosis as compared to patients from European-American descent. We believe that the differences in DNA mutations at these 17,000 “DNA switches” may make the tumor behave differently between these patient groups. Overall, our studies will greatly improve our understanding of the biology that drives lethal metastatic prostate cancer and explain the differences in prognosis between patients from different ethnic backgrounds. These results will reveal novel therapeutic avenues tailored to the unique biology of the tumor and also represent a major step towards curative treatment of metastatic prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110234
Entities
People
- Matthew L Freedman
Organizations
- Dana–Farber Cancer Institute
- United States Army