Career Goals: My career goal is to build upon my medical and graduate training to use the power of genomics, a tool that allows us to systematically analyze the genetic changes of cancer, to discover and study new genes responsible for aggressive prostate cancer. My goal is to then translate these discoveries into new diagnostic tests and targeted therapies to improve the survival of patients with prostate cancer. I will pursue rigorous scientific training in molecular biology and genomics under the mentorship of Dr. Levi Garraway in his laboratory at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and the Massachusetts Institute of Technology. My clinical training in prostate cancer will take place at the Dana-Farber Cancer Institute under the co-mentorship of Dr. Philip Kantoff, an international expert in prostate cancer. My training plan includes participation in scientific and clinical meetings and protected time to pursue the research proposed in this application while also building clinical expertise by caring for prostate cancer patients in the clinic. My research plan is focused on investigating the mechanisms of African-American prostate cancer and will provide opportunities to translate discoveries in the lab into improved care for all patients with prostate cancer. The research and training program proposed in this application will fulfill my career goal to be an academic physician-scientist and ultimately lead a laboratory devoted to the advancement of research and care of prostate cancer patients.

Scientific Objective and Rationale: Prostate cancer is the most common cancer in men and the second most common cause of cancer-related death. However, many men with prostate cancer have indolent disease that will not affect their life expectancy. African-American men are more likely to get prostate cancer and more likely to die from their prostate cancer than Caucasian men. The biological mechanisms behind these differences are unknown, though there is some evidence that genetic changes in these tumors play a role. We now have the ability to systematically sequence the DNA of cancers to identify genetic changes that only occur in tumors and are not found in a person's normal DNA. Since African Americans seem to have more aggressive prostate cancers, by cataloguing the genetic changes found in prostate cancers in this population we can determine whether there are particular genetic changes responsible for the poor clinical outcomes in this group. Once we have identified particular genetic alterations that occur frequently in our study group of African-American men with prostate cancer, we will design a sequencing tool to test larger populations of African-American men with prostate cancer for these specific genetic alterations to see if they are correlated with high-risk, aggressive disease. We hypothesize that by focusing on African-American prostate cancer, we will be able to find new genes that drive the development of prostate cancer. Using this approach in our preliminary sequencing data from a cohort of African-American prostate cancer samples, we have identified a new gene that is recurrently mutated in prostate cancer in this group. Through this grant, we plan to study how this gene works and whether it contributes to the development of aggressive prostate cancers.

Applicability of the Research: The research described in this proposal will advance our knowledge of the genetic changes that drive prostate cancer and, in particular, help identify the genes and genetic changes responsible for high-risk, aggressive disease. These studies will significantly inform our understanding of prostate cancer within African-American men, a group at higher risk for aggressive disease. The research project involves studying a gene that when mutated may drive the development of prostate cancer. These studies may lead to new understandings of prostate cancer biology and pave the way for new therapeutic targets. Developing a catalog of genetic changes that occur in African-American prostate cancer will tell us if specific genetic changes can distinguish aggressive from indolent disease. One potential clinical application is the development of a tumor profiling approach to rapidly sequence prostate tumors at the time of diagnosis. If we can identify genetic mutations in tumors that are indicative of aggressive disease, then we have the opportunity to improve our treatment of patients by directing them to more aggressive treatment. It is possible that such a test could be available in the next 3 years given the rapid advancement that sequencing technologies have made in the clinic and our increasing knowledge of tumor genetics. From the studies in this proposal, we will advance our knowledge of prostate cancer, informed by the diversity of the American population that suffers from prostate cancer with the goal of improving survival for all patients with prostate cancer.