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Tiny RNA; big results
NEW HAVEN, Conn.—Using a mouse model, researchers from Yale University and Austin, Texas-based Mirna Therapeutics Inc., have reversed the growth of lung tumors through the use of a naturally occurring microRNA (miRNA) with tumor suppression abilities. With lung cancer being both a prevalent and very hard-to-treat cancer, the news is promising for the oncology community and patients alike, showing, as Yale and Mirna put it, that "a tiny bit of RNA may one day play a big role in cancer treatment."
"This is the first time anybody has shown a positive effect of microRNAs in shrinking lung cancer," asserts Dr. Frank Slack, one of the senior author of the paper, a researcher at the Yale Cancer Center, and a professor of molecular, cellular and developmental biology there.
The Yale-Mirna team, which focused on non-small-cell lung cancer (NSCLC), published its results in the Dec. 7 issue of the journal Oncogene. In the article, they report that tumors in mice with NSCLC shrank after the Yale team delivered a type of miRNA called let-7 through intranasal dosing.
As Slack and fellow senior authors Dr. Joanne B. Weidhaas of Yale and Dr. Andreas G. Bader of Mirna note, research has increasingly shown that miRNAs—small bits of genetic material most often associated with transmission of information encoded in DNA—play crucial roles in gene regulation and gene silencing. This research helps bolster the growing belief that miRNAs could become useful as therapeutics.
As they note, the idea is for let-7 to be a "replacement therapy" rather than a traditional "medicine."
"Similar to targeted therapies that tackle a gain of function in cancer, such as epidermal growth factor receptor inhibitors, reintroduction of the let-7 tumor-suppressor miRNA interferes with the oncogenic properties of tumor cells and induces a therapeutic response," Mirna's Bader and the other writers note. "In contrast to an inhibitory approach, however, 'miRNA replacement therapy' seeks to restore the expression and function of a naturally occurring molecule. Hence, miRNA replacement therapy represents a unique therapeutic opportunity following a different strategy than small-molecule inhibitors, small interfering RNAs and miRNA antagonists, and deserves further exploration."
Looking specifically at the results of the recent research, the Yale team found that mice without let-7 developed cancer, supporting their hypothesis that the microRNA acts as a tumor suppressor. The tumors in mice that received let-7 were not eliminated, but were reduced by 66 percent.
Slack noted let-7 is absent in many cancers and acts upon a gene known to play a role in about a quarter of all human cancers, so he doesn't see NSCLC or lung cancer in general as an endpoint by any means.
"We hope it will be valuable in the treatment of many other forms of cancer," he says.
Next on the schedule, and already in progress in fact, for the team is to study whether let-7 therapy in combination with chemotherapy and radiation can actually induce full remission.
Another challenge and goal moving forward is to refine the delivery method. As the team notes, local delivery of synthetic let-7 by intra-tumoral injections resulted in strong inhibition of overall tumor growth.
"However, this delivery route might be inadequate in a clinical setting as peripheral tumor cells remained present and showed limited knockdown of let-7 targets by immunohistochemistry," they wrote. "Therefore, a delivery technology that facilitates universal access to all tumor cells, such as a systemic delivery route, might be needed to make a let-7 therapeutic more efficacious."