Small-Molecule Targeting of RNAs 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. Another class of molecules, “non-coding RNA,” has also recently been implicated in the progression of prostate cancer as well as the development of resistance, but no Food and Drug Administration (FDA)-approved drugs exist to specifically target these processes. 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. In some cases, the RNA message does not serve as a blueprint at all but rather acts independently in ways similar to proteins. The importance of these types of non-coding RNA is only beginning to be realized. We have developed a method to generate drug-like small molecules that are targeted specifically toward RNA and have been successful in selective RNA binding. We will apply these technologies to (1) bind the misprocessed sites of the messenger RNA to inhibit alternative splicing associated with prostate cancer aggressiveness and (2) bind noncoding RNA and inhibit its activity in aggressive prostate cancer. Objective: The objective of this research is to identify small molecules that target and alter RNA events that drive prostate cancer aggressiveness. Aims: We will achieve this objective by first targeting two alternatively spliced RNAs that show different types of processing in aggressive African American versus less aggressive white prostate cancer. We will specifically identify small molecules that change processing to the less aggressive form of genes like LMO7, which contribute to prostate cancer growth and metastasis. Next, we will use our technology to target part of a noncoding RNA, MALAT1, which is found at high levels in resistant prostate cancer and is also thought to impact alternative splicing. We have already developed selective ligands for this RNA and will optimize them for reduction of proliferation and invasion in prostate cancer cells. From these studies we will be able to evaluate whether inhibition of race-related splice variants and/or non-coding RNA 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 or non-coding RNA, 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 RNA events in cell culture systems is a critical first step toward treating the disease in live animal models and ultimately in human patients. Indeed, these RNAs may prove to be more specific targets, i.e., have fewer side effects, than many protein targets. In addition to allowing novel therapeutic routes to be evaluated, the ability to alter splicing and non-coding RNA activity 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
- Mar 10, 2021
- Source ID
- W81XWH2010188
Entities
People
- Amanda E Hargrove
Organizations
- Duke University
- United States Army