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Q&A: TGen's Glen Weiss on microRNAs as Lung Cancer Biomarkers


Glen Weiss

Director, thoracic oncology, TGen Clinical Research Services
Clinical assistant professor, medicine, University of Arizona College of Medicine

• Fellow, hematology/medical oncology, University of Colorado Health Sciences Center — 2004-2007
• Resident, internal medicine, SUNY-Downstate — 2001-2004
• MD, Sackler School of Medicine — 2001
• BA, biology, Rutgers College — 1997

Researchers from the Translational Genomics Research Institute, in collaboration with the Van Andel Research Institute and Scottsdale Healthcare, last week published data showing that elevated tumor levels of a particular microRNA, miR-92a-2*, were associated with chemoresistance and decreased survival in patients with small cell lung cancer.

The findings, which appeared in the Journal of Thoracic Oncology, suggest that the miRNA may have potential as a patient-screening biomarker "in an effort to design more tailored clinical trials for this subpopulation," according to the study's authors.

This week, Gene Silencing News spoke with the paper's senior author Glen Weiss about the results.

Let's start with some background on you and your research focus.

My research focus on the clinical end is drug development and finding new therapies for patients with advanced cancer, and I have a specialization in lung cancer. On the laboratory side, my focus is looking at lung cancer in terms of improving therapies, identifying predictive or prognostic markers, with a special focus on the utilization of microRNAs.

Could you provide an overview of the study and the findings?

One of the key issues for patients with small-cell lung cancer, which affects approximately 33,000 US patients annually, is that there have not been a whole lot of new treatments of therapies for these patients.

The standard therapy is to get a platinum-based chemotherapy with either etoposide or irinotecan, and for a majority of those patients [receiving this therapy], the results are initially good. But they usually become resistant to therapy and the cancer comes back, and most of the patients die of their disease. In a small fraction of patients who get that chemotherapy upfront, they have no response or rapidly progress, and their outcome is significantly poorer.

The main idea of this study was to try to identify the group that has the worst outcome. One of the key issues in the clinical realm is that we don't have great ways of sorting those patients out, so all patients get treated with the same type of chemotherapy for this particular lung cancer.

So we went through the clinical records at Scottsdale Healthcare … of patients with small-cell lung cancer, and determined survival [rates] for those patients [who] received chemotherapy and if they had a response to therapy. We then analyzed tumor samples related to those patients and performed microRNA-expression profiling to see if we could identify a few key microRNAs that might stratify the group with the better results and the group with the poorer outcomes.

What we found were three microRNAs that were significant for resistance to therapy. Of those three microRNAs, we also looked to see if there was any relationship to survival amongst the various clinical factors and the microRNAs that came out. At least one of them was significantly associated with both chemoresistance and poor survival: miR-92a-2*.

What are the next steps then?

This is the first type of study that deals with microRNAs in this particular type of lung cancer patient, response and resistance to therapy, and outcome. Because it was in a small group of patient samples, we need to validate this in a much larger setting, and that's what we're focusing on next. [We'll be] looking at other datasets and patient samples to see if we can validate this in a larger group.

If we can do that, this might lead to a new way of thinking about designing clinical trials for these patients so we can look at the tumor, get an assay developed, look at the microRNAs [and see if they] tell us if the patient is going to have a good response or poor response. Then, [the patients] would be stratified accordingly.

If we can find or develop a new drug that works in poor-risk patients better than standard therapy, that might lead to a new way of treating this particular niche of small-cell lung cancer patients.

As far as getting access to a greater number of samples for analysis, is that something that will involve other institutions?

We are pursuing other collections, not at TGen or Scottsdale Healthcare. We'd like to validate in a different population of patients that were treated somewhere else. That holds the most muster, if we can validate outside of our clinical practice.

You talk about possibly finding a drug that would work in patients with poor outcomes. Does that include compounds targeting miR-92a-2*?

There are currently several companies exploring the use of microRNAs as therapeutics. If those clear the initial human studies to show that that strategy is promising, then certainly these biomarkers could be considered for therapeutics.

The way to develop those is a little more complicated, [however], so the first focus is to try to use them as biomarkers.

Assuming follow-up work is promising, what does the path toward using this microRNA as a biomarker clinically look like? Is this something that would be done with a commercial partner?

Probably it would be best suited to partner with a commercial entity.

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