Tiny RNA; big results

Yale and Mirna researchers show that microRNAs can shrink lung tumors

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NEW HAVEN, Conn.—Using a mouse model, researchers from YaleUniversity and Austin, Texas-based Mirna Therapeutics Inc., have reversed thegrowth of lung tumors through the use of a naturally occurring microRNA (miRNA)with tumor suppression abilities. With lung cancer being both a prevalent andvery hard-to-treat cancer, the news is promising for the oncology community andpatients alike, showing, as Yale and Mirna put it, that "a tiny bit of RNA mayone day play a big role in cancer treatment."


"This is the first time anybody has shown a positive effectof microRNAs in shrinking lung cancer," asserts Dr. Frank Slack, one of thesenior author of the paper, a researcher at the Yale Cancer Center, and aprofessor of molecular, cellular and developmental biology there.


The Yale-Mirna team, which focused on non-small-cell lungcancer (NSCLC), published its results in the Dec. 7 issue of the journal Oncogene. In the article, they report that tumors in micewith NSCLC shrank after the Yale team delivered a type of miRNA called let-7through intranasal dosing.


As Slack and fellow senior authors Dr. Joanne B. Weidhaas ofYale and Dr. Andreas G. Bader of Mirna note, research has increasingly shownthat miRNAs—small bits of genetic material most often associated withtransmission of information encoded in DNA—play crucial roles in generegulation and gene silencing. This research helps bolster the growing beliefthat miRNAs could become useful as therapeutics.


As they note, the idea is for let-7 to be a "replacementtherapy" rather than a traditional "medicine."


"Similar to targeted therapies that tackle a gain offunction in cancer, such as epidermal growth factor receptor inhibitors,reintroduction of the let-7 tumor-suppressor miRNA interferes with theoncogenic properties of tumor cells and induces a therapeutic response,"Mirna's Bader and the other writers note. "In contrast to an inhibitoryapproach, however, 'miRNA replacement therapy' seeks to restore the expressionand function of a naturally occurring molecule. Hence, miRNA replacementtherapy represents a unique therapeutic opportunity following a differentstrategy than small-molecule inhibitors, small interfering RNAs and miRNAantagonists, 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 theirhypothesis that the microRNA acts as a tumor suppressor. The tumors in micethat received let-7 were not eliminated, but were reduced by 66 percent.


Slack noted let-7 is absent in many cancers and acts upon agene known to play a role in about a quarter of all human cancers, so hedoesn'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 otherforms of cancer," he says.

Next on the schedule, and already in progress in fact, forthe team is to study whether let-7 therapy in combination with chemotherapy andradiation can actually induce full remission.


Another challenge and goal moving forward is to refine thedelivery method. As the team notes, local delivery of synthetic let-7 byintra-tumoral injections resulted in strong inhibition of overall tumor growth.


"However, this delivery route might be inadequate in aclinical setting as peripheral tumor cells remained present and showed limitedknockdown of let-7 targets by immunohistochemistry," they wrote. "Therefore, adelivery technology that facilitates universal access to all tumor cells, suchas a systemic delivery route, might be needed to make a let-7 therapeutic moreefficacious."


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