microRNA replacement in malignant pleural mesothelioma

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Published: 26 Jun 2014
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Dr Glen Reid - The University of Sydney, Sydney, Australia

Dr Reid talks to ecancertv at WIN 2014 about microRNA replacement as a therapeutic option for malignant pleural mesothelioma. Tests on animals have shown this method to inhibit tumour growth so early stage clinical trials are now in progress.

 

 

I’ve come here to the WIN symposium to present some of our work which has been focussed mostly on microRNA replacement as a therapeutic option for malignant pleural mesothelioma. What we’ve done there is we’ve identified microRNAs that are strongly down-regulated in the tumour cells and in vitro first we put these back with synthetic mimics and found strong inhibition in the tumour cells. Then we’ve teamed up with a biotech company called EnGeneIC to deliver these microRNA mimics in animals. We again found that there was strong down-regulation or strong inhibition of tumour growth in the animals so we’re moving on now to early stage clinical trials with this approach.

What are microRNAs?

MicroRNAs are very short pieces of RNA which generally regulate the expression of other genes. They’re termed the master regulators of various processes. They basically keep cells in a differentiated state and, like other genes in cancer, they can be either oncogenes or tumour suppressor genes. Because they tend to down-regulate other genes when they’re lost these genes can be turned on so they’re typically tumour suppressor in their activity in cancer. In malignant pleural mesothelioma itself we find that a lot of the genes that have previously been found to be up-regulated in this cancer are controlled by the microRNAs that we’ve found down-regulated. So that fits in the story of the biology of this tumour.

What did the study entail?

In the study we took some samples from patients undergoing surgery for malignant pleural mesothelioma, this is an asbestos related cancer with poor prognosis. We took those and we analysed the microRNA expression. We found that these tumour suppressor microRNAs were down-regulated. We weren’t the first to identify these as tumour suppressor microRNAs, they were already known in lung cancer, for instance. But we were the first to show this in mesothelioma.

What other tumours would you find this in?

It’s also in non-small cell lung cancer, also in prostate cancer, but this was the first time that we saw that in malignant pleural mesothelioma.

What’s the next step?

At the moment we’re busy getting all the ‘t’s crossed and ‘i's dotted to get the clinical trial underway. It’s going to be a phase 0/phase I trial. We’re looking at biodistribution and also optimal dose of the experimental therapy which is a mini-cell containing the microRNA mimic which is targeted with an antibody to EGFR which is frequently over-expressed in mesothelioma. So the next stage is, of course, to see what happens in this trial. We’re quite hopefully that we won’t have any toxicity issues because the delivery agent has been used in patients before. So we’re already planning for the phase II trial of efficacy of this experimental therapy. We’ve also looked at other microRNAs in our studies and we’re now looking at combinations of different microRNAs to see whether we get a synergistic effect when we combine mimics to replace the expression of these down-regulated microRNAs.

What about toxicity?

With the phase 0/phase I probably… we don’t expect any toxicity because the delivery agent has been used extensively in patients before. We’re only changing it by putting in a microRNA which on its own won’t have any toxicity. We’re hoping that we will be able to use a high level optimal dose that we can then take on to the next trials.

What are some of the other details about the trial that we should know about?

It’s interesting in itself that it’s only the second trial of a microRNA replacement therapy to start in the world. There’s one trial underway at the moment looking at replacing microRNAs in liver cancer but this is the first in thoracic cancer and the first using a microRNA based on the miR-16 family, which is the one we’re interested in at this point.

What would be your take home message for clinicians?

The only take home message I could give from the research we’ve been doing is that it’s of course very important to involve basic researchers and clinicians in the same study. We have worked together quite closely with the surgeons in Sydney who are responsible for carrying out the radical surgery on mesothelioma patients. We also work closely with pathologists and medical oncologists and also we work a lot with other people interested in this disease. So we have a truly collaborative and translational approach which I think helps a lot.