Elevated Uracil Glycosylase Coupled to Reduced Base Excision Repair Promotes AA PCa Progression
Abstract
Rationale: African American (AA) males have a higher incidence of PCa, are more likely to be diagnosed at a younger age, and often present with more advanced and aggressive disease. While there are risk factors associated with the development of AA PCa, we lack detailed mechanisms about the unique tumor biology in AA PCa, which contributes to the disparity in outcomes from these patients. The low enrollment of AA patients in clinical trials and the socioeconomic factors that impact their diagnosis, care, and outcomes have created significant challenges in acquiring sufficient data and models to understand AA PCa and develop targeted therapeutics. We have established a cross-disciplinary research team containing experts in DNA damage (Gassman), PCa and health disparities (Sreekumar), PCa clinical management (Rao), and prostate pathology (Ittmann) to address the Prostate Cancer Research Program’s overarching challenges to define the biology of lethal prostate cancer to reduce death and to develop treatments that improve outcomes for men with lethal prostate cancer with the long-term goal of reducing the disparity in survival outcomes for AA PCa patients. Scientific Objective: We have generated novel preliminary data using patient samples that demonstrate AA tumors have metabolic changes (resulting from changes in major metabolic pathways) that create an imbalance in uracil nucleotides (these are small molecules and metabolites that are an integral part of RNA, but should not be seen in the genomic DNA) within the tumor cells, leading to uracil DNA damage. Further, we have determined that the DNA repair proteins in the base excision repair pathway (BER), which excise the base, in this case, uracil, and repair the DNA associated with repairing uracil lesions within the genome are dysregulated (or function suboptimally) and fail to remove the uracil from the genome (or DNA). From these data, we hypothesize that metabolically induced elevation of uracil lesions coupled with reduced BER promotes progression in AA PCa tumors. In other words, we believe that increase in uracil caused by altered metabolism coupled to reduced ability of the tumor cells to repair uracil containing DNA damage can result in increased mutations that drive AA PCa. Clinically, this suggests that AA PCa, which cannot repair DNA damage, is more responsive to inhibitors targeting DNA repair pathways. Furthermore, it also suggests that a lower ability to repair damaged DNA indicated by lower expression of the protein XRCC1 in AA tumors could be used to stratify patients who would be most responsive to PARP inhibitors. Clinically, PARP inhibitors such as rucaparib are in phase 2 trials for men with advanced prostate cancer (see Transition document). Overall, this proposal leverages clinical data from AA and EA tumors to develop improved cell line models that recapitulate metabolic and DNA repair differences seen in patient samples. We will use these models to dissect biological features unique to AA tumors that may allow targeted therapeutic intervention in the near future. The mechanistic data generated by this proposal will support the targeted use of PARP inhibitors for AA PCa patients that show dysregulated BER from metabolic reprogramming. Clinical Translation and Population Benefit: At the conclusion of this study, we will establish a strong rationale for treating AA men with low XRCC1 expressing PCa with PARP inhibitor. With the clinical biomarkers identified by this work, Dr. Rao will develop the phase 1b/2 trial of biomarker-selected prostate cancer patients to prospectively investigate the role of our proposed biomarker in inducing PARP inhibitor sensitivity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210135
Entities
People
- Natalie Gassman
Organizations
- United States Army
- University of Alabama at Birmingham