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Australian Asbestos Research Institute Plans microRNA Drug Trial in Mesothelioma

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With the support of a A$1.2 million (US$1.1 million) donation, Australia's Asbestos Diseases Research Institute is poised to begin human testing of a microRNA-based treatment for malignant mesothelioma, a form of cancer triggered by the chronic lung inflammation that results from asbestos exposure.

Although asbestos-related diseases occur worldwide, Australia has the highest incidence of malignant mesothelioma globally on a per capita basis, in part because the mineral was mined and widely used in building products in the country, according to ADRI researcher Glen Reid.

Having worked in the small RNA field before, including as head of RNAi product development at the nearly-defunct Genesis Research & Development, Reid had been interested in exploring the role of miRNAs in malignant pleural mesothelioma, an "invariably fatal" condition with no known cure.

One of the treatment options available is a radical surgery called extrapleural pneumonectomy, which involves the removal a diseased lung, as well as portions of the diaphragm, parietal pleura, and pericardium.

Reid said that ADRI established a relationship with an Australian surgeon who has been conducting these operations for more than 20 years, and as a result has built a significant collection of formalin-fixed, paraffin-embedded malignant mesothelioma tumor tissue.

With these samples, he and his colleagues began studying miRNA signatures of patients to validate potential biomarkers of the cancer that they had already identified in plasma.

"One of the interesting things we found was that one of the microRNAs we used as a normalizer … miR-16, was significantly downregulated in all the tumors we looked at," he told Gene Silencing News. "We went on and looked at a larger set [of tumors], comparing them with normal tissue, and indeed miR-16 was very much downregulated … in mesothelioma tissue."

Additional investigation showed downregulation of miRNAs in the miR-16 family were suppressed in the cancer tissue — a notable finding as both miR-16 and family member miR-15 have been linked to different cancers by various other groups.

Using malignant mesothelioma-derived cell lines, Reid and others at ADRI began testing the effects of miR-16 and miR-15 mimics, and found that such treatment inhibited cell growth and induced apoptosis. "We could also sensitize [the cells] a little bit to chemotherapies," he added.

Looking to test the findings in vivo, Reid began collaborating with Engeneic, an Australian biotech firm that has developed a delivery vehicle for small molecules and nucleic acids.

Called EDVs, the delivery particles are based on bacterial minicells and can be targeted to specific tumor cells through the addition of bispecific antibodies on their surfaces, according to Engeneic. Earlier this year, the company completed a phase I trial of chemotherapy-loaded EDVs, which showed that the delivery approach is safe and well tolerated.

With the Engeneic technology, ADRI researchers delivered synthetic miR-16 and miR-15 mimics into mouse xenograft models of malignant mesothelioma and "got quite striking [tumor] growth inhibition," Reid said. The results, in fact, were "far in excess of what have been seen with other experimental therapies in the same model, so we were quite excited to go forward."

He noted that the data from these studies has been submitted to the Annals of Oncology and are expected to be published in the coming months.

In terms of a clinical candidate, Reid and his team have opted to use a single molecule to replace all miR-16 family members, rather than individual constructs for each of the seven miRNAs.

"We've created a sort of consensus sequence based on the entire family," he explained. This single oligo has features of all the different miRNAs, and "seems to have higher growth-inhibitory potential" than mimics of any individual one.

The drug will be delivered using Engeneic's vehicles, and will incorporate antibodies for epidermal growth factor receptor, which mesothelioma, like a number of other cancers, expresses on its surface.

Clinical testing is expected to begin before year-end.

Unlike most other clinical trials, however, ADRI's study will begin with a six-patient phase 0 portion — a relatively new stage of clinical testing that is designed to examine the pharmacodynamics and pharmacokinetics of an exploratory therapy. Because these studies involve subtherapeutic doses, they yield no safety or efficacy data.

Assuming a positive outcome of this arm of the trial, the study is designed to enroll an additional 24 patients in a phase I portion that will examine safety and tolerability of the drug.

Reid noted that although malignant mesothelioma patients are the target patient population for the treatment, the study will also be open to those with non-small cell lung cancer — laying the groundwork for expanding the drug's use should it prove effective.

"There are papers from others that have shown good tumor-suppressor activity of miR-15 and miR-16 in lung cancer, as well as prostate cancer," he said. "Any tumor that has lost expression of these microRNAs would be a candidate for similar treatment."

Reid said that the A$1.2 million bequest supporting the trial came from a malignant mesothelioma patient who died in 2011. The funding is expected to be sufficient to allow ADRI to run the phase 0/I study on its own.

Additional clinical testing, he added, would likely require the support of an industry partner.

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