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Q&A: NYU Langone Medical Center's Harvey Pass on miR-29c* and Mesothelioma Prognosis

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pass_smaller.jpgName:
Harvey Pass

Position:
•Professor, cardiothoracic surgery, NYU Department of Surgery
•Chief of thoracic surgery, NYU Langone Medical Center

Background:
• Professor, surgery/oncology, Wayne State University — 1996-2005
• Head, thoracic oncology section and surgery, National Cancer Institute — 1986-1996
• Assistant professor, surgery, University of Health Sciences — 1983-1996
• Assistant professor, surgery, Medical University of South Carolina, Charleston — 1982-1983
• MD, Duke University Medical School — 1973

Researchers from Rosetta Genomics, in collaboration with investigators from New York University's Langone Medical Center, this week published data in Cancer Research demonstrating that a single microRNA, miR-29c*, could be used as a prognostic biomarker in patients with mesothelioma.

In the study, miRNA expression levels in 142 malignant pleural mesothelioma tumors were analyzed using Rosetta's proprietary miRNA-based array and qRT-PCR technologies, according to the company. "The results clearly demonstrate that higher levels of miR-29c* in MPM predict a more favorable prognosis. Not only was the microRNA able to separate MPM patients by time to progression after surgery, but it also stratified these patients by their survival," it added.

Expression levels of miR-29c* could also be used to identify groups of patients with different time to progression of the disease, as well as differing survival rates, Rosetta noted. "Furthermore, the study found that over-expression of miR-29c* in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion and colony formation," it said.

This week, RNAi News spoke with NYU Langone Medical Center's Harvey Pass, a co-author of the study, about the findings.

Let's start with a little about you and your work at NYU.

I'm the chief of thoracic surgery at NYU and I am funded by the [Department of Defense, Centers for Disease Control and Prevention, and the National Cancer Institute] for biomarker discovery in both lung cancer and mesothelioma.

Has that included work with microRNAs before, or is this the first time you're looking at the small RNAs?

When I came to NYU four years ago, I knew I wanted to get into microRNAs. I had been using genomics and Ingenuity [Pathway Analysis] to look at pathways and describe extracellular markers, and microRNAs were intriguing to me.

I have a gigantic archive of surgical specimens from when I was at [the National Cancer Institute and] when I was at Karmanos [Cancer Institute of Wayne State University], and now at NYU. I've looked at many parameters in the [mesothelioma samples] as far as prognosis and early diagnosis, and I thought [examining] microRNAs would be a reasonable thing to do.

I met with [Rosetta Genomics] and we established a relationship. [Previously], there was another paper that came out from Rosetta that has to do with miR-205 and distinguishing squamous cell carcinoma from [non-squamous, non-small cell lung cancer], and we were part of that effort.

But this [effort] was one that was truly new to [Rosetta] with regard to really looking at mesothelioma globally and having a number of specimens with excellent demographics to really explore.

Is just getting specimens a common hurdle for this kind of work?

It's a very common hurdle to get specimens. The next hurdle is: if you want to get them onto a new platform or a new technology, what do you do? Do you look online at companies that are doing microRNA [research], do you buy your own stuff, do you see if a core is doing [this kind of work]?

On the advice of other people whom I have a great deal of respect for, I decided to do [this work] as an industry/university partnership.

Can you give an overview of the research detailed in Cancer Research?

Mesothelioma is variable with regard to its prognosis. The majority of patients will die within 12 months of the diagnosis. There are patients who have a more indolent type of mesothelioma and live for a long time, but the majority of [sufferers] will have explosive disease and will not even be capable of being operated on.

I am a surgeon, so I had specimens on all the patients I have operated on, and I have been using them for my research. So I knew when [the tumors] occurred after I operated, I knew when [the patients] died, and the basic hypothesis was that there would be expression profiles of miRs that would tell us who was going to live longer than a certain time or [whose disease] was going to recur longer than a certain time.

Using [Rosetta's] platform to look at [about] 800 microRNAs, we did a training set and a test set, and found consistent data between the two with regard to one specific microRNA that seemed to have prognostic importance.

And it was the microRNA's up-regulation that correlated with a favorable outcome?

Yes. It's a good thing to have this microRNA. Mesothelioma is a very complicated tumor with regard to what asbestos does to cells. We know that there are changes in genomics, there are changes in epigenetics, there are changes in glycosylation patterns with this disease, and all of those seem to make it very difficult to understand — and I've looked at all of those.

What we found was that [when] this microRNA … was present in the patients, they lived longer, stage for stage. The bottom line is, in a multivariate analysis, this miR was an independent predictor of survival.

Now, the question is: what does the miR do? Through a series of transfection experiments, we looked at certain things that made sense from targets we got from the [Wellcome Trust Sanger Institute's miRBase] database, and we found that this miR controls those things that are involved in methylation of mesothelioma — the DNA methyltransferases.

The presence of this miR down-regulates DNA methyltransferases and up-regulates genes like adiponectin and others that are associated with active demethylation. So our hypothesis is that we've got a microRNA that, at the epigenetic level, seems to have control, and the less methylated you are, the better you seem to do.

How do you envision these findings playing out in a clinical setting?

There are other issues that are being investigated, [such as whether] this microRNA also has involvement with chemotherapy sensitivity, and we're looking at that.

[Another consideration is] if you have a patient [with mesothelioma, and] you do a biopsy and you find this microRNA down-regulated, would you operate on a patient like that? It's a big operation, and if the role of surgery in those patients is questionable. You may want to treat with chemotherapy or other modalities first before committing them to a giant operation. So [the miRNA's expression] may very well stratify patients as to how you're going to treat them in the future.

What other sort of work is going on to on follow up on these findings?

This [work was done] in snap frozen tissue, and our plan [with Rosetta is to validate the findings] in formalin-fixed tissue. Obviously, we will be looking not only at [miR-29c*] but other miRs that may have additive value. And we'd like to expand the profile and hopefully have [a procedure] that could be [Clinical Laboratory Improvement Amendments]-certified. But that is for the future.

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