The Jarrard Laboratory Group is focused on several understudied aspects of epigenetic tumor biology.
One question addresses the role of epigenetics and prostate cancer susceptibility with aging. The epigenome is susceptible to modulation by many factors associated with aging, including dietary and oxidative stress. We have found that the peripheral zone of the prostate from men with prostate cancer commonly contains biallelic Igf2 expression (Clin Can Res 1996), and that an age-related degradation of imprinting occurs in the murine and human prostate (JBC2007: Can Res 2009). A loss of CTCF binding protein during aging underlies the relaxation in Igf2 imprinting seen during aging (Prostate 2011) and furthermore is accelerated with oxidative stress linking the environment to epigenetic changes (Plos One 2014). This has led to a broader study of DNA methylation alterations as biomarkers for cancer (Neoplasia 2013; J Urol 2014). Thus, a degradation of the epigenome occurs which leads to a field of cancer susceptibility in the prostate serving as a marker for the disease, as well as a potential avenue for therapy.
Other areas of research involve identifying novel histone modifications and their enzymes in prostate cancer progression (ACS Chem Biol.2017) allowing a personalized medicine approach to prostate cancer therapy.
Other research interests encompass improving the outcomes of patients with high-risk prostate cancer. I was the urology co-PI on the ECOG 3805 CHAARTED trial that resulted in the publication of the paradigm shifting 2015 JAMA article demonstrating that metastatic hormone-sensitive prostate cancer patients treated with androgen deprivation therapy (ADT) and docetaxel led to a remarkable 14-month improvement in survival. Our funded research has sought to improve responses to androgen deprivation through the study of synthetic lethality. We were the first to define a novel cell response, that of cellular senescence, that occurs in response to ADT (Prostate 2013; PloSOne 2017). A Department of Defense grant I lead has screened and identified drugs that synergistically improve outcomes when used with ADT. This led to work demonstrating that in 87,000 veterans taking metformin at the time of initiating ADT for advanced prostate cancer there was an improved cancer-specific and overall survival (HR 0.70, 95% CI 0.64-0.77; J Urol 2018). Metformin targets metabolic susceptibilities that ADT induces in the tumor and further investigation of this phenotype reveals other FDA-approved synergistic agents that have minimal toxicity (J Urol; 2018). Our work initiated and provides a rationale for the combined use of ADT with other agents in the treatment of metastatic HSPC – now a standard of care.
Our clinical research seeks to improve the outcomes for high risk prostate cancer by utilizing new approaches in imaging and combination therapy. We have ongoing trials examining the use of chemohormonal therapy (funded through the Dept. of Defense) prior to surgery to remove the prostate. Utilizing newer PSMA-PET imaging functions provide a new way of looking at disease prior to treatment as well as treatment response. On the other end of the cancer spectrum, we have been employing molecular approaches to better inform clinical trials looking at the prevention of prostate cancer (Eur J Cancer Prev 2016; Am J Clin Exp Urol 2016).
David F Jarrard, MD also serves as PI on several national clinical trials and brings a translational cancer focus to the program.