MicroRNA inhibitors halt cancer cell growth

JUPITER, Fla.—In early March, scientists at the Disney Lab of The Scripps Research Institute (TSRI) announced they had designed two new drug candidates to target prostate and triple-negative breast cancers. The new research, published recently as two separate studies in ACS Central Science and the Journal of the American Chemical Society, demonstrates that a class of drugs called small-molecule RNA inhibitors can successfully target and kill specific types of cancer.

“This is like designing a scalpel to precisely seek out and destroy a cancer—but with a pill and without surgery,” said Dr. Matthew D. Disney of the Department of Chemistry at TSRI’s Florida campus, who was senior author of both studies. In their ACS Central Science study, Disney and his colleagues used DNA sequencing to evaluate thousands of small molecules as potential drug candidates. The researchers were on the lookout for molecules that could bind precisely with defective RNAs.

This strategy led them to a compound which targets an RNA precursor molecule. Disney tells DDNews, “Targapremir-18a is a small-molecule drug that binds to a precursor to microRNA 18a. The compound inhibits the production of microRNA 18a, which is overexpressed and causative of prostate cancer.”

The scientists found that mature microRNA-18a inhibits a protein that suppresses cancer. When microRNA-18a is overexpressed, cancers just keep growing.

Disney and his team tested Targapremir-18a, and found that it could target microRNA-18a and trigger prostate cancer cell death. “Since microRNA-18a is overexpressed in cancer cells and helps to maintain them as cancerous, application of Targapremir-18a to cancer cells causes them to kill themselves,” Disney said.

“[Targapremir-18a] was tested in cancer cells isolated from patients. The compound silences the microRNA selectively, and causes prostate cancer cells to go into apoptosis or programmed cell death,” Disney continues. “[Next] we are planning to test the compound in mouse models.”

The precise binding of Targapremir-18a to microRNA-18a means a cancer drug that follows this strategy would be likely to kill prostate cancer cells without causing the broader side effects seen with many other cancer therapies, according to Disney.

And there may be even bigger implications. “We could apply the strategy used in this study to quickly identify and design small-molecule drugs for other RNA-associated diseases,” explained study first author Sai Velagapudi, a research associate in Disney’s lab.

Disney says Targapremir-18a and another agent, Targapremir-210, “both act by the same mechanism, and that is to bind to a precursor of these microRNAs and inhibit their production.” The same screening strategy used to find Targapremir-18a led the researchers to a drug candidate to target triple-negative breast cancer, as reported in the Journal of the American Chemical Society.

Triple-negative breast cancer is especially hard to treat because it lacks the receptors, such as the estrogen receptor, targeted with other cancer drugs. Disney and his colleagues aimed to get around this problem by instead targeting microRNA-210, which is overexpressed in solid breast cancer tumors.

The researchers tested their drug compound, Targapremir-210, in mouse models of triple-negative breast cancer. They found that the therapy significantly slowed tumor growth. In fact, a single injected dose decreased tumor size by 60 percent over a three-week period. The researchers analyzed these smaller tumors and discovered that they also expressed less microRNA-210, compared with untreated tumors.

Targapremir-210 appears to work by reversing a circuit that tells cells to “survive at all costs” and become cancerous. With microRNA-210 in check, cells regain their normal function and cancer cannot grow. “We believe Targapremir-210 can provide a potentially more precise, targeted therapy that would not harm healthy cells,” said study first author and TSRI graduate student Matthew G. Costales.

When asked if researchers plan to bring these drugs to trials in the near future, Disney says, “Yes, we are assessing compound toxicity and gearing up to get funding to advance these molecules for a clinical trial. We are searching for partners to accelerate these investigations.” The researchers also plan to further develop their molecule-screening strategy into a platform to test molecules against any form of RNA defect-related disease.