Small molecule RNA inhibitor shows promise in PCa

Targeted treatment with a small molecule RNA inhibitor demonstrates promising activity for promoting apoptosis of prostate cancer cells in culture, report investigators from Scripps Florida.

New research demonstrates that targeted treatment with a class of drugs called small molecule RNA inhibitors can successfully target and kill certain types of cancer, including prostate cancer.

In a recently published study, the treatment demonstrated promising activity for promoting apoptosis of prostate cancer cells in culture, reported investigators from Scripps Florida in a recently published study (ACS Cent Sci 2017; 3:205-16).

The compound, known as Targapremir-18a, inhibits the activity of microRNA-18, an oncogenic noncoding RNA that is overexpressed and causative in prostate cancer. Acting as a “dimmer switch,” microRNA-18 enables cancer cells to proliferate by circumventing the programmed cell death pathway.

In the in vitro experiment, the addition of Targapremir-18a to cultured DU145 prostate cancer cells resulted in increased synthesis of the proapoptic protein that corresponded to increased apoptotic cell death.

Next: "The ultimate question we are trying to address is, how quickly can we get this to patients?”

“Targeted treatment for cancer aims to improve efficacy and safety by using agents that are tumor specific because they modulate gene networks that are selectively upregulated in tumor cells but not in healthy tissue,” said senior author Matthew D. Disney, PhD, of The Scripps Research Institute, Scripps Florida, Jupiter.

“Our work with the microRNA-18a inhibitor is an advance in this type of precision medicine because it represents the first demonstration of a small molecule inhibitor successfully targeting an oncogenic noncoding RNA in prostate cancer cells. Moving ahead, we are working to optimize the molecule so that it will be effective when tested in vivo in an animal model. The ultimate question we are trying to address is, how quickly can we get this to patients?”

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Dr. Disney and colleagues in his laboratory have been working for more than 10 years to design small molecules that act as selective inhibitors of oncogenic noncoding RNAs. Their search is based on a reverse assay approach. It begins with the creation of small molecules that are screened for their binding profiles to a library of about 100,000 small RNA motifs, which do not necessarily have any known association with cancer. Positive interactions are mined against genomic RNAs to identify lead therapeutic candidates using a computational approach created by Dr. Disney and colleagues.

“In identifying Targapremir-18a as a possible treatment for prostate cancer, we did not develop it with the aim of targeting prostate cancer. Rather, prostate cancer found us through our screening process in which we found that Targapremir-18a bound with high affinity and selectivity to microRNA-18A,” Dr. Disney told Urology Times.

Dr. Disney and colleagues have already developed other small molecule RNA inhibitors as potential targeted treatments for other types of cancers that have demonstrated promising activity when tested both in vitro and in animal models. Small molecule RNA inhibitors are also being developed as targeted treatments for other RNA-associated diseases.