Project: Clinical Utility of Prostate Cancer Genetic Risk Assessment with the Polygenic Risk Score in African American Men with Elevated Prostate Specific Antigen

Principal Investigators: Claire de la Calle, MD and Christian Pavlovich, MD

Year 2 Summary: With the funds we have obtained from the Schaufeld Program, we were able to launch a clinical trial (GenBx trial) aiming to evaluate the role of germline genetic testing (meaning testing of the genes we inherit from our parents) in men with elevated PSA (i.e., at risk of harboring prostate cancer,) specifically in men of African ancestry.

For this trial we are obtaining the genetic risk score (GRS), a score based on hundreds of minor alternations in the human genetic code (DNA) called single nucleotide polymorphisms (SNPs).Prospective validation of the GRS is still needed and the tes tneeds to be calibrated in cohorts of African ancestry, which is why we launched the GenBx trial in July 2022. We have been enrolling patients for 12 months now have 120 men registered, of which 30% are of African ancestry. Most previously published study cohorts had much smaller proportions of men of African ancestry. GenBx is a multi-institutional trial (patients are also being accrued at Northwestern and Northshore hospitals), and nearly 300 patients have been enrolled across the three sites. Our goal is to enroll 1,000 patients total across all three sites, and we hope to reach this goal in 3-4 years. We also plan to evaluate the GRS in 500 men of African ancestry using men enrolled in GenBx and by sequencing men already in the Johns Hopkins biorepository.

Additional Leveraged Support: Dr. Sean Fletcher, one of our urology residents, was able to obtain a Patrick C. Walsh grant in order to fund the sequencing of men of African ancestry in the Johns Hopkins biorepository. This has allowed us to build on initial funding received from the Schaufeld Program.

Project: Androgen Receptor-Mediated Regulation of Innate Immunity in Metastatic Prostate Cancer in Black Men

Principal Investigator: Janielle Maynard, PhD

Year 2 Summary: We investigated androgen receptor (AR)expression and immune cell infiltration in prostate cancer tissues. Differential AR expression was observed by race in both primary and metastatic tissues, but there was no apparent influence of grade, PTEN loss, or ERG expression on AR expression. Our multi-staining analysis identify few immune cells that express AR. However, our quantitative image analysis demonstrated that AR expression is correlated with immune cell infiltration in both primary and metastatic tissues. Interestingly, mast cells specifically had differential correlations between races.

We also observed altered immune infiltration between races in our metastatic tissues. Our findings thus far indicate a complex relationship among AR expression, immune infiltration, and race that warrant further investigations.

Next Steps: A pilot spatial sequencing project using AR-positive and -negative metastatic tissues from Black and White men is ongoing. This allows us to assess the influence of AR status on immune cell infiltration, inflammation-related genes, and other critical genes involved in prostate cancer metastasis while taking race into consideration. Successful completion will prove feasibility, which is a prerequisite for larger grant applications to support the analysis of a larger cohort.

Project: Biological Differences as a Driver of Aggressive Disease

Principal Investigator: Tamara Lotan, MD

Year 2 Summary: During the past year, we published an initial study on how chromosome copy number varies by self-identified race or genetic ancestry in primary prostate cancer. This study highlighted a number of new genomic regions that are differentially lost or gained in primary prostate tumors from Black compared to White men, and also identified which of these regions are associated with development of metastases in these tumors. This study is particularly important because Black men have been woefully under-represented in most other genomic studies of prostate cancer and almost no previous studies of Black men have included clinical follow-up for metastatic disease. Currently, we are extending this work to look at which epigenomic alterations vary by race and are associated with outcomes in Black men. Epigenomic alterations such as DNA methylation are molecular alterations to the DNA that do not change its fundamental coding sequence, but have pronounced effects on how the DNA is transcribed to messenger RNA and eventually forms proteins. These types of alterations are particularly interesting because they are heavily influenced by the surrounding environment, and may reflect diet, environmental exposures and other factors that could be influenced by social determinants of health.

Additional Leveraged Support: In collaboration with Dr. Karen Sfanos, we submitted a P20 grant application, which is a feasibility study for a larger P01 award, to examine the effects of race on immunotherapy response in prostate cancer, including efforts to improve participation among Black men in ongoing immunotherapy trials for this disease. This grant application heavily leveraged current efforts by the Schaufeld program and wouldn’t have been possible without it.

Project: Urinary Detection of Prostate Cancer in Black Men: A Pilot Howard/Hopkins Collaboration

Principal Investigator: Jun Luo, PhD

Year 2 Summary: Schaufeld funding continues to enable my team to expand the scope of our research. My laboratory is developing methods for early detection of aggressive prostate cancer, including genetic testing, that can be applied to high-risk populations such as Black men. Our dedicated efforts have brought together urologists in the Baltimore area who are high-volume providers.

Additional Leveraged Support: We submitted two external grant applications with these doctors proposing to enroll self-reported African American men into our studies. We secured funding from the Department of Defense Congressionally Directed Medical Research Program to investigate a mutation that puts African American men at higher risk for aggressive prostate cancer. We are also setting up collaborations with urologists in Jamaica to broaden the applicability of the lab results.