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Australian Team Finds Blood miRNA with Potential for Early Diagnosis of Malignant Mesothelioma

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Blood levels of the microRNA miR-625-3p could serve as a predictive biomarker for the early diagnosis of malignant pleural mesothelioma, according to research by a group from the Concord Hospital Asbestos Diseases Research Institute in Sydney, Australia.

The team reported its findings from a small discovery and validation study of miRNAs in blood plasma in a presentation at the third European Lung Cancer Conference last month. The researchers also plan to publish a fuller account of the study in an upcoming issue of the Journal of Thoracic Oncology.

Study leaders Glen Reid and Michaela Kirschner told Gene Silencing News this week that the team's initial results were encouraging, but require further validation in larger sample cohorts.

The group found that miR-625-3p was four times more abundant in the blood of mesothelioma patients than in healthy controls, and could distinguish the disease with 82 percent accuracy.

Reid said that limited access to samples led the group to start small, with only five mesothelioma patients for their discovery set, and 15 to validate. For this reason, the performance of miR-625-3p, as well as the potential of two other miRNAs that did not reach statistical significance, will have to be replicated in larger sample sizes.

However, the researchers believe the initial positive results bode well for developing a potential clinical diagnostic, which could circumvent treatment delays associated with the need for biopsies. "We're not saying it absolutely will become a diagnostic marker based on this study alone, but perhaps with further validation studies, [miR-625-3p] could prove to be clinically useful," Reid said.

Rosetta Genomics currently markets a miRNA-based diagnostic for distinguishing mesothelioma from other lung cancers. The ADRI team's effort is more directed toward early diagnosis of the disease, the researchers explained in their conference abstract.

The team is now continuing its research in a larger group of serum samples from a local clinical trial and also plans to collaborate with colleagues in the Netherlands to study additional European samples. Reid said the researchers also plan to study the biology of miR-625-3p with the hope that it might emerge as a potential therapeutic target.

The group's first steps, which Kirschner discussed at the April conference, were spurred by a perceived lack of molecular biomarkers and new therapeutic targets in malignant mesothelioma.

"We looked at what was already available and there wasn’t much." Reid said. "There are proteins that are available you can measure in patient serum, but they're not that powerful."

At the time, he added, interest in circulating miRNAs in other cancers was growing, along with research on miRNA expression levels in mesothelioma tumors versus normal tissue. The ADRI researchers decided to profile plasma from five mesothelioma patients and three healthy controls using Agilent miRNA microarrays. This discovery group showed 17 miRNAs with significantly greater abundance in the disease samples versus controls.

The group then validated this subset of miRNAs using quantitative real-time PCR in a set of 15 mesothelioma samples and 12 controls.

"Through this we found miR-625-3p to be present at quite increased levels in the [mesothelioma] patients' plasma, about four-fold," Kirschner said. "It also showed an accuracy of about 82 percent" in distinguishing between disease and control samples, she explained.

The validation set also showed two other miRNAs — miR-29c* and miR-92a — were present at higher levels in disease samples but the difference was not statistically significant.

Finally, the researchers examined a second validation group of 30 mesothelioma patients and 10 patients with asbestosis. The group found that miR-625-3p was able to distinguish between the two diseases with 79 percent accuracy. Reid said this distinction is important, since many patients at risk for mesothelioma will also have asbestosis due to asbestos exposure.

According to Reid, while the two additional miRNAs the group found to be elevated in mesothelioma samples were not significant predictors in the early research, it's possible they may show stronger power in studies of larger cohorts.

"We haven’t ruled out the possibility that any potential diagnostic test in the future would be a signature rather than a single miRNA," he said.

He added that the ADRI team isn't interested in commercializing an eventual diagnostic itself. Rather, the researchers plan to take their study as far as they are able, and then look to outsource commercial development "at the appropriate time," he said.

As a side project, the group is also now looking into the functional biological role of miR-625-3p as a potential drug target, after finding that the miRNA is expressed at higher levels in mesothelioma tumor tissue in addition to being more abundant in blood plasma.

A paper describing the biomarker profiling study was recently accepted for publication in the Journal of Thoracic Oncology, Reid added, and the group expects it to appear some time in the next few months.

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