Deciphering DDX3-Mitochondrial Axis in Prostate Cancer Ethnic Disparity
Abstract
Prostate cancer is the second most prevalent cancer in men. However, prostate cancer rates are substantially different depending on race, ethnicity, and geographic location. These disparities can be explained not only by genetic predispositions, but also by dietary factors, environmental factors, lifestyle habits,, access to care, etc., which in various combinations drive the development of biologically aggressive disease. However, the impact of many of these factors is poorly understood due to the complexity of their underlying biological influence on prostate cancer biogenesis. Even though men of African descent (Afro-Caribbean, Sub-Saharan African, and African American [AA]) have the highest prostate cancer mortality rates, the confounding factors that contribute to this mortality rate are still largely unknown. Substantial epidemiological studies have shown associations with genetic predisposition; but overall, common origins for these disparities have not been well defined. Recently, associations between mitochondrial biology and the racial disparities exhibited in prostate cancer have been gaining momentum. Strong evidence has been emerging that indicates that mitochondrial-associated metabolism and its effect on nuclear genes have a prominent role in prostate cancer development. There is empirical proof that AA cancer patients presenting with different cancer types, including prostate, have increased mitochondrial activity, which could form the basis of the treatment-responsive disparity in prostate cancer clinical outcomes seen in AA patients. In parallel with this hypothesis, we have data to indicate that an RNA helicase, DDX3, is overexpressed in AA prostate cancer patients compared to European American (EA) counterparts. Importantly, we have already demonstrated that DDX3 is crucial for mitochondrial activity and is essential for oxidative phosphorylation (OXPHOS), a product of mitochondrial respiration. Significantly, we have developed a small molecule inhibitor of DDX3 (RK-33) that exhibits anti-tumor effects in multiple preclinical models of cancer. With respect to expression of DDX3 in AA prostate cancer samples, we have immunohistochemical data to indicate that there is enhanced DDX3 expression in AA men with Gleason scores of 6 and 7 compared to EA men. This is important, as it indicates that, during early tumor biogenesis in AA men, DDX3 is a contributor to aggressive phenotype. In addition, one of the prostate cancer cell lines generated from an AA prostate cancer patient, MDA-PC-2b, overexpresses DDX3 and is very sensitive to the DDX3 inhibitor we developed. Collectively, the involvement of DDX3 in mitochondrial biogenesis, energy production, apoptosis, and signaling could contribute to prostate cancer etiology and potentially address the disparity issue of enhanced prostate cancer mortality observed in the AA population. In this proposal, we will define how DDX3 expression enhances prostate cancer aggressiveness in AA men and correlate it to the underlying genetic landscape to identify novel druggable targets in combination with the DDX3 inhibitor we developed that potentially demonstrates ethnic/race-enhanced drug response. Our long-term goal is to use DDX3 as a biomarker for aggressive prostate cancers in AA men with the intention of targeted therapy that will reduce patient morbidity and enhance the quality of life. This will also facilitate better management of prostate cancer patients, leading to improved quality of life, and reduce the morbidity associated with lethal prostate cancers in AA men and other high-risk populations. Notably, we will attempt to address the health disparity issue of why there is an enhanced prostate cancer rate and aggressive phenotype at presentation in AA men. Finally, we are of the opinion that the development time required to bring RK-33 into clinics will be between 3 to 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010254
Entities
People
- Venu Raman
Organizations
- Johns Hopkins University
- United States Army