Targeting castration-resistant prostate cancer by engineering 3 untranslated region
Abstract
The development and growth of prostate cancer requires the continuous presence of testosterone and related hormones. As a result, most prostate cancer therapies over the past 40 years have been designed to limit the production of testosterone or to block its activities within prostate cancer cells. These standard therapies are very effective for a period of months to years. Unfortunately, most prostate cancers eventually become resistant to these treatments, progressing to a stage that is hormone-resistant and particularly lethal for patients. The most pressing goal of prostate cancer research is to better understand the lethal stage and to develop alternative strategies to combat it. We have compared early-stage and lethal-stage prostate cancers using a cutting-edge technology to analyze a type of molecule known as messenger RNA (mRNA) and have discovered a unique feature of lethal prostate cancer: mRNA molecules from lethal prostate cancer are significantly shorter than mRNA molecules from early-stage prostate cancer, particularly on one side, known as the 3 prime untranslated region (3’ UTR). It is particularly interesting because it specifically occurs in the most untreatable stage of the disease. It is not yet clear how this phenomenon impacts prostate cancer cell behavior, but we hypothesize that it may provide a growth advantage. We have observed that some of the shortened mRNA molecules are linked to “oncogenes,” or genes that influence cells to behave in a more cancer-like way. It seems plausible that shortening these molecules may enhance the effect of these oncogenes and contribute to lethality. To learn whether this phenomenon is reversible or treatable, it is critically important to develop an experimental treatment that reverses this phenomenon in lethal prostate cancer cells. Increasing the length of specific oncogenic mRNA molecules has not been previously accomplished by researchers; however, we have developed a new mRNA editing technology for this exact purpose. In this proposal, we will test the hypothesis that mRNA shortening promotes lethal prostate cancer progression and that our new mRNA editing technology can increase the length of key mRNA molecules and thereby inhibit the growth of lethal stage prostate cancer. This research relates to two FY19 PCRP Overarching Challenges: “Define the biology of lethal prostate cancer to reduce death” and “Develop treatments that improve outcomes for men with lethal prostate cancer.” The ultimate applicability of this research is to improve the treatment of lethal prostate cancer by testing the efficacy of a new strategy to increase the length of key mRNA molecules. Our newly developed mRNA editing technology has the potential to lengthen key mRNA molecules not only to allow us to test our ideas in the laboratory, but potentially to treat lethal prostate cancer in a clinical context as well. By the end of the two-year funding period, we will find out how mRNA shortening influences lethal prostate cancer biology as well as the consequences of reversing this phenomenon in lethal prostate cancer in the laboratory. We will inform the larger research community about the outcomes of this study and its clinical applicability through detailed research publications. My entire career has been dedicated to the goal of running an independent research group to understand the basis of prostate cancer development and the means by which we can combat this disease. In this project, I will focus on understanding the role of mRNA shortening within the 3’ UTR that occurs during prostate cancer progression to the lethal stage. The proposed research plan will provide a basis for my future investigations of how 3’ UTR length becomes shorter in lethal prostate cancer and for movement of our new mRNA editing technology forward to clinical trials. During my fellowship, my mentors will meet with me frequently to discuss experimental design, write articles to dissemina
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010068
Entities
People
- Fuwen Yuan
Organizations
- Duke University
- United States Army