Targeting Neuroendocrine Prostate Cancer by Engineering 3 Untranslated Regions
Abstract
For decades, the treatment of advanced prostate cancer has depended upon the removal of the patient’s testosterone through either surgery or drug treatment. While this strategy effectively prolongs life, it rarely provides a cure, as most cases of advanced prostate cancer eventually progress to a lethal stage called “castration-resistant” prostate cancer (CRPC). The development of better testosterone-blocking drugs has successfully delayed the progression of CRPC even further; however, CRPC remains incurable. Among CRPC patients who have benefitted from long-term anti-testosterone treatment, clinicians have seen a concerning rise in the incidence of an extremely aggressive form known as neuroendocrine prostate cancer (NEPC). NEPC is rapidly fatal and has no known effective treatments. The first step in developing a treatment will be to identify which molecules inside NEPC cells are responsible for encouraging their growth. We have used a cutting-edge technology to study a diverse group of molecules called messenger RNAs (mRNA) and have discovered a unique feature: mRNA molecules from NEPC are different than mRNA molecules from other advanced prostate cancers in that they are significantly longer on one side, known as the 3 prime untranslated region (3’UTR). This is particularly interesting because we only detect it in the most untreatable stage of the disease. However, it is not yet clear whether it is responsible for transforming prostate cancer into NEPC or how it influences the success or failure of medical treatment. Our preliminary experiments indicate that 3’UTR lengthening may provide a growth advantage, since some of the lengthened mRNA molecules are linked to “oncogenes,” or genes that influence cells to behave in a more cancer-like way. Lengthening these molecules may enhance the effects of these oncogenes and contribute to NEPC lethality. To learn whether 3’UTR lengthening is reversible or treatable, we must develop an experimental treatment that reverses this phenomenon in NEPC cells. Shortening the length of 3’UTR of specific oncogenic mRNA molecules has not been previously accomplished by researchers due to technical limitation; however, we have developed a new mRNA editing technology for this exact purpose (US Provisional Patent Application No. 62/873,270, patent pending). In this proposal, we hypothesize that 3’UTR lengthening enables prostate cancer to develop into NEPC. We also propose that our new mRNA editing technology can shorten the length of the 3’UTR of key mRNA molecules and thereby block the growth of NEPC cells. We will test the biological functions of genes with abnormally long 3’UTR in NEPC cell culture systems and in mice with NEPC tumors and will study these genes in tumor samples from human patients with NEPC or other stages of prostate cancer. We will also test whether cancer-like behaviors can be blocked after the long 3’UTR of key genes are shortened by our newly-invented mRNA 3’UTR editing technology. This research addresses two FY19 PCRP 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.” The application of this research is to improve the treatment of NEPC by testing the efficacy of a new strategy to decrease the length of 3’UTR of key mRNA molecules. By allowing us to shorten key mRNA molecules, this technology will not only facilitate completely new discoveries in the laboratory, but could potentially be used in the future to treat NEPC patients as well. By the end of the 3-year funding period, we will find out how 3’UTR lengthening influences NEPC biology, as well as the consequences of reversing this phenomenon in NEPC in the laboratory. We will inform the larger research community about the outcomes of this study and its potential clinical applications by publishing and sharing all findings.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010183
Entities
People
- Qianben Wang
Organizations
- Duke University
- United States Army