In African American (AA) men prostate cancer is characterized by higher aggressiveness, more extensive metastases, early onset, and increased mortality rates compared to those in Caucasian men. We propose to evaluate role of PDEF (Prostate Derived Ets Factor) and TWIST-1 in PCa health disparity. The studies proposed in this application are driven by our novel observations that there is graded decrease in PDEF levels in prostate cancer cells with increasing aggressive phenotype and in prostate cancer tissue sections of patients. We also observed in multiple clinical data sets that PDEF mRNA expression is decreased in high Gleason grade PCa and in tumor metastasis. Moreover we observed a reciprocal relationship between PDEF and Twist-1 expression in PCa tissues and that PDEF and Twist-1 expression could predict PCa patient survival. In preliminary studies we observed that PDEF expression is decreased in prostate cancer cells from AA men and in cells with aggressive phenotype, and experimental modulation of PDEF expression modulates cell migration and clonogenic activity in part by promoting luminal differentiation. These exciting preliminary data form the basis of our proposed hypothesis: First, that, ? In African American Men PDEF could serve as a functional marker for distinguishing aggressive prostate cancer from an indolent disease.? Second that ?PDEF functions as a metastasis suppressor in prostate cancer in part by modulating expression of Twist-1?, and third that ?Loss of PDEF can help us stratify PCa patients that might respond to DNA methyl transferase inhibitors?. We propose three aims to test these hypothesis.
AIM 1 : To establish differences in expression levels of PDEF between grade-matched Prostate Cancer specimens from African American and Caucasian men and correlate these with patient outcomes;
AIM 2 : To determine the role of PDEF in PCa metastasis and racial disparity using in vivo model systems, and ; *AIM 3: To evaluate if prostate cancers with PDEF loss respond more favorably to combination of ADT (Enzalutamide) and DNA methyl-transferase inhibitors (azacytidine and decitabine) as compared to ATD alone. The proposed studies are innovative as these will enhance understanding of role of PDEF in suppressing prostate cancer metastasis and help us evaluate usefulness of PDEF/Twist-1 in early detection of patients that may harbor aggressive prostate cancer with enhanced metastatic potential. The impact of our study will be on the development of a new method to distinguish aggressive and metastatic phenotype of prostate cancer from an indolent disease, which will particularly benefit AA men, and reduce ethnic disparity in in prostate cancer treatment outcomes.
In African American (AA) men prostate cancer is characterized by higher aggressiveness, early onset, more extensive metastases, and increased mortality rates compared to those in Caucasian men. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no effective treatment for intervention in metastatic prostate cancer. Currently-used prognostic indicators (Digital rectal exam, PSA measurement and Gleason score) do not predict metastases risk accurately. These facts underline the urgent, yet unmet, need for identification and characterization of new targets that can help distinguish between aggressive and metastatic prostate cancer from an indolent disease. Our goal is to address this vital knowledge gap by characterizing the role of Prostate Derived Ets Transcription Factor (PDEF) in PCa aggressiveness, thereby reducing the prostate cancer-related health disparity between African American (AA) and Caucasian men. We propose a novel and unique causative link between PDEF and metastases. Our proposal also details mechanistic experiments that may help to patient stratification and use PDEF expression as a means to stratify patients to demethylating agents. Our studies will pave the way for routine clinical use of PDEF as an independent predictor of metastases risk.
