image: TSRI Professor Matthew Disney led both studies on the Florida campus of The Scripps Research Institute. (Photo by James McEntee.) view more
Credit: The Scripps Research Institute
JUPITER, FL - March 9, 2017 - Scientists on the Florida campus of The Scripps Research Institute (TSRI) have 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 new 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 TSRI Professor Matthew Disney, senior author of both studies.
A Tool to Fight Prostate Cancer
RNAs are molecules that translate our genetic code into proteins. RNA defects can lead to cancers, amyotrophic lateral sclerosis (ALS), myotonic dystrophy and many other diseases.
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--like keys fitting in the right locks.
This strategy led them to a compound that targets the precursor molecule to an RNA called microRNA-18a. This RNA had caught the attention of scientists who 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 their compound, called 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.
Disney said 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.
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 the Disney lab.
Testing the Strategy in Breast Cancer
The same screening strategy 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. The Disney lab aimed to get around this problem by instead targeting an RNA called 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 down tumor growth. In fact, a single 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 TSRI Graduate Student Matthew G. Costales.
Next, the researchers plan to further develop their molecule-screening strategy into a platform to test molecules against any form of RNA defect-related disease.
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Additional authors of the ACS Central Science study, "Defining RNA?Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA," were first author Sai Pradeep Velagapudi, Yiling Luo, Tuan Tran, Hafeez S. Haniff, Yoshio Nakai, Mohammad Fallahi, Gustavo J. Martinez and Jessica L. Childs-Disney of TSRI.
The research was funded by the National Institutes of Health (grant R01-GM097455).
Additional authors of the Journal of the American Chemical Society study, "Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit," were Christopher L. Haga, Sai Pradeep Velagapudi, Jessica L. Childs-Disney and Donald G. Phinney of TSRI.
The study was supported by the National Institutes of Health (grant R01GM9455) and a Scheller Graduate Student Fellowship.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine -- work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu.
Journal
ACS Central Science