Stroma-Based Prognosticators Incorporating Differences between African and European Americans
Abstract
Compared to European Americans (EA), African Americans (AA) suffer a much higher incidence of prostate cancer, at an earlier age, and have a more aggressive form of the disease. Here we propose to take steps to mitigate some of these critical problems for AA patients that arise from this disparity. We were the first to use differences in the activity of genes in the genetically more normal tissue surrounding tumors, called stroma, in order to predict which of the patients that undergo prostate removal would later still develop deadly metastatic disease. While tumor cells contain a seething mass of unstable genetic changes, stroma cells are genetically virtually normal. However, the activity of these normal genes in tumor-adjacent stroma is greatly changed by the tumor, and we have shown that these differences correlate with how aggressive the tumor is. We have exploited these changes in gene activity in the stroma to develop a predictor of metastatic disease with an accuracy as high as 90%. However, despite prostate cancer being more common in AA, the patient population used to develop our predictor contained very few AAs. Therefore, our predictor has been less adequately tested for AA patients compared to EA patients. Here we propose to use more cases of AA to optimize the performance of our predictor for AA. We found that AA and EA differ in the activity of many genes in the stroma tissue surrounding the tumor. These differences in gene activities might be related to the higher incidence, earlier age of onset, and/or the more severe disease commonly found in AA patients. We will study whether the activities of these genes correlate with the outcome of disease in AA and/or EA. In the long term, studying genes whose activity is correlated with disease progression will help us to better understand the underlying reasons for the differences in AA and EA prostate cancer. In addition, these genes will arm us with targets for developing new treatments. We will use three ways to measure the activity of genes that may predict disease outcome. We will look at expression of RNA, DNA methylation (a chemical modification of the DNA that changes gene activity) and protein expression. These methods are established in our lab and each of these methods has unique strengths as possible predictors. The goal is to develop and validate a set of gene activity changes that predicts disease outcome for AA patients. Our predictor will provide precise risk scores for each patient, so that those in need of aggressive therapy can be more reliably identified, and perhaps given anticancer drugs in addition to prostate removal. Both AA and EA will benefit, but AA may benefit more than EA because of the greater incidence, earlier onset, and the overall more aggressive prostate cancer in the AA population. Reliable identification of specific patients for aggressive treatment has a substantial impact. Predictors like the one we are trying to improve gain Food and Drug Administration approval more quickly than new drugs or devices. Thus, once reliable predictions can be identified, applying the predictors to new patients could begin immediately upon completion of this 3-year project. Continuing examination of the success of the method going forward takes place in what is called a "prospective study." The time to a substantial impact of our research on health for AA patients may therefore be very short.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510696
Entities
People
- Michael Mcclelland
Organizations
- Naval Information Warfare Center Pacific
- United States Army