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Chemoprevention Study Identifies miRNA-34c as Potential Surrogate Endpoint for Future Trials

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A team from the University of Colorado Cancer Center has identified a microRNA, miR-34c, that could potentially serve as a surrogate endpoint for trials of lung cancer chemopreventives.

According to the group, the finding — published last month in Cancer Prevention Research — is not conclusive and needs to be confirmed in larger studies. However, the initial results suggest that miR-34c could potentially allow researchers or clinicians to assess the efficacy of chemopreventive treatments without waiting the years necessary to measure overall reduction in mortality.

Fred Hirsch, the study's senior author, told Gene Silencing News this week that his team is planning to re-examine miRNA-34c's association with histological changes in the lung in another chemoprevention study his team is conducting.

The researchers are also planning to try to identify miRNAs that can be used as an adjunct to radiographic lung cancer screening tools to reduce false-positive rates.

In the recent study, informed by previous research showing that several miRNAs were correlated with changes in lung tissue in the development of cancer, Hirsch and his colleagues set out to see if they could identify a miRNA that was associated with response to the investigational chemopreventive drug iloprost.

Overall, Hirsch said, the development of chemopreventive drugs is far behind the world of lung cancer treatments. This is largely because trials of chemoprevention requires long follow-up periods – often more than a decade – to assess the affect of drugs on overall cancer mortality.

"These types of studies are just not very suitable for looking into new drugs," which he said is frustrating because "with the knowledge of molecular biology today related to lung carcinogenesis, there are a lot of potential drugs out there."

In the group's iloprost study — a randomized phase II trial comparing the drug to placebo published last year in Cancer Prevention Research — the researchers found that among a subgroup of patients who were former, but not current smokers, treatment with iloprost was associated with improvement in the histology of lung biopsy samples.

Interested in finding more quantitative tools to assess efficacy than histological change, or potentially to predict best responders to the drug, the group decided to use the opportunity of the iloprost trial to explore miRNAs as potential intermediate endpoint or predictive markers.

Based on previous research by Hirsch's colleague Celine Mascaux, the study's first author, the group chose 14 miRNAs to assess in the125 iloprost study samples.

Mascaux had tracked miRNA expression in the early stages of lung cancer progression, beginning with 374 miRNAs and narrowing that down to 69 that were differentially expressed during the transition from early dysplasia to lung cancer, publishing the results in the European Respiratory Journal in 2009.

Based on these findings, Mascaux, Hirsh, and their co-authors chose 14 miRNAs to test in the iloprost trial samples using TaqMan microRNA assays.

None of the 14 miRNAs the group examined showed an association with response to the drug over placebo sufficient to predict responders, according to the authors. But one, miR-34c, was inversely correlated with baseline histology, and also with changes in the histology of biopsy samples after treatment at six months follow-up.

This indicated that the molecule "could be a biomarker for the quantitative measure of histological response and a potential intermediate endpoint in lung cancer chemoprevention trials," the authors wrote.

Hirsch said the group has not studied the biological role of miR-34c extensively yet, but in the paper, the authors wrote that the members of the miR-34 family are direct targets of p53, and thus are "key players in apoptosis and cell-cycle arrest.”

Studies of miR-34c in rats have shown that the molecule becomes down-regulated after exposure to cigarette smoke, according to the group.

In Mascaux's previous study of lung cancer progression, the team also saw that miR-34c was down-regulated in normal human bronchial biopsies of smokers compared to those who never smoked, and that it became further and further down-regulated through the successive steps of lung cancer development.

According to Hirsch, his team is currently working to confirm miR-34c's correlation with histology improvement in a trial of another chemopreventive drug from the same drug class. He did not share further details of this study.

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