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Colorado Study Yields miRNA Marker with Potential as a Surrogate Endpoint in Chemoprevention Trials


Using samples from a study of an experimental chemopreventive drug, iloprost, a team from the University of Colorado Cancer Center has identified a microRNA, miR-34c, that could potentially serve as a surrogate endpoint in lung cancer trials for gauging patients' long-term outcomes on chemopreventive agents.

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 PGx Reporter 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 with a different drug.

Overall, Hirsch said, the development of chemopreventive drugs is far behind the world of lung cancer treatments. This is largely because trials of chemoprevention require 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," Hirsch said, adding that this 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 miRNA study, Hirsch's team was initially searching for promising biomarkers either for use as intermediate endpoints, to allow more rapid assessment of new chemopreventive treatments, or to specifically predict which patients would respond to iloprost and which would not.

Iloprost is an approved treatment for pulmonary hypertension, which has shown promise in preclinical studies in preventing the development of lung cancer. The drug is marketed by Actelion Pharmaceuticals as Ventavis in the US.

In the group's initial iloprost study — a randomized phase II trial comparing the drug to placebo published in 2011 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.

According to the researchers, improvement in histology is not an established intermediate or surrogate endpoint for chemoprevention, though it is a logical one.

However, interested in finding more quantitative tools to assess efficacy, or potentially 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 the 125 iloprost study samples.

None of the 14 miRNAs the group examined showed an association with response to the drug over placebo, according to the authors. But one, miR-34c, was inversely correlated with baseline histology, and 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.

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 became further and further down-regulated through the successive steps of lung cancer development.

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

He said the team is also interested in looking at miR-34c and a larger group of miRNAs in a separate study of lung cancer early detection. The researchers hope the miRNAs might be able to help reduce false positives in early-detection radiographic imaging screening techniques.