Small Molecule Targeting of RNA Splice Variants Driving Tumor Aggressiveness
Abstract
Rationale: Treatment of advanced prostate cancer is hampered by the inability to easily identify the aggressive forms of the cancer and by the surprisingly few effective therapies. Recently, a cell process termed "alternative splicing" has come to the forefront as a driver of the aggressiveness found in prostate and other cancers. Our work has shown that differences in alternative splicing events are key factors between the more aggressive prostate cancer often seen in African American men and the less aggressive prostate cancer of white men. In the cell, DNA codes are first turned into RNA "messages" that the protein producing machinery then uses as a blue print to construct the protein. In alternative splicing, the DNA of a cell remains the same, but the processing (splicing) of the RNA message is altered. This change in RNA processing changes the blueprint and produces a different protein, which can have damaging effects, such as increased cancer growth and metastasis. We have developed a method to generate small molecule chains that are targeted specifically toward RNA and have been successful in selective RNA binding. We will apply these technologies to bind the misprocessed sites of the messenger RNA to inhibit alternative splicing associated with prostate cancer aggressiveness. Objective: The objective of this research is to identify small molecules that target and alter splicing events that drive prostate cancer aggressiveness. Aims: We will achieve this objective by starting with a well-understood alternative splicing system, namely Bcl-x, whose misprocessing is known to contribute to the ability of cancer cells to avoid natural cell death. Because the activity of Bcl-x is so well understood, it is an ideal choice for us to develop our RNA-binding technology. We will next apply these techniques to inhibit an aberrant splicing event, namely, the production of the AR-V7 protein, which is thought to enable prostate cancer cells to avoid the effects of Enzalutamide, one of the most currently used treatments. Lastly, we will use our technology to change the relative levels of alternatively spliced genes found to exist at different levels in more aggressive African American prostate cancer versus less aggressive white prostate cancer. From these studies, we will be able to evaluate whether inhibition of race-related splice variants may represent novel therapeutic targets relevant to prostate cancer patients of all races. Impact: Because the technologies developed here could potentially be applied to any alternative splicing event, nearly all victims of prostate cancer, as well as other cancers, will benefit from the success of this project by providing new treatments and increasing our understanding of prostate cancer progression. While it will likely be several years before these types of approaches are used in the clinic, developing the principles of small molecule targeting of splicing events in cell culture systems is a critical first step toward treating the disease in live animal models and ultimately in human patients. In addition to allowing novel therapeutic routes to be evaluated, the ability to alter splicing will allow researchers to understand how these events impact tumor growth and invasion as well as other important biological processes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610589
Entities
People
- Amanda E Hargrove
Organizations
- Duke University
- United States Army