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Q&A: TGen's Glen Weiss on Identifying microRNA Biomarkers for Chemotherapy Resistance


Glen Weiss

Director, thoracic oncology/clinical assistant professor of medicine, TGen Clinical Research Services

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

Earlier this month, Glen Weiss, a researcher at the Translational Genomics Research Institute's Clinical Research Services group, presented data detailing how a group of three microRNAs — miR-92a-2*, miR-147, and miR-574-5p — were found to be up-regulated in small-cell lung cancer patients resistant to front-line therapy.

"For patients with small-cell lung cancer, there are really only two chemotherapy options," Weiss said in a statement. "We need to be more precise with our treatments and identify who is going to be resistant up front in order to design better clinical trials that will identify effective therapies for these at-risk patients."

This week, RNAi News spoke with Weiss about his findings, which were presented at a joint conference of the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Let's start with an overview of the research you do.

One of the focuses of my lab is to utilize microRNAs essentially as theranostics — for diagnosis, prognosis, predictive use, and potentially therapeutic use down the road. We focus primarily on lung cancer, both non-small-cell lung cancer and small-cell lung cancer. I'm also a clinician and work in drug development.

An issue with drug development and clinical trials is to identify the right patient for the right drug. [For] small-cell lung cancer, there have not been many new breakthroughs in the last 10 to 15 years, and all patients are essentially treated the same up front, and we know that roughly 15 to 30 percent of those patients that get treated with front-line therapy don't respond and do pretty poorly.

So I am trying to find ways of identifying those patients, other than from clinical parameters, that could ultimately lead to a well-designed clinical trial where we can test new drugs versus the standard. Hopefully that new drug is effective … for that group of [non-responding] patients.

You were looking at small-cell lung cancer in this study. What's the front-line treatment for that?

Front-line therapy is platinum-based, and is either cisplatin or carboplatin. In North America primarily, the other drug that is combined with one of these drugs is etoposide. Another drug that is sometimes used is irinotecan.

Can you give an overview of the study presented at the conference?

We looked at all the archival tissue samples at our local hospital, Scottsdale Healthcare, and when there was tissue available and clinical information that went along with it, we selected those patients that were confirmed to have received chemotherapy.

Then we looked at how they responded to chemotherapy. We extracted the RNA, did microRNA-expression profiling on those samples, and came up with potential candidates that differentiated those with a good prognosis or poor prognosis, and response or resistance to chemotherapy. Using those markers, we proceeded with PCR to validate the expression array, and came up with three microRNAs that appear to be associated with what we're calling de novo chemo-resistance.

These are diagnostic specimens, and in those, the microRNA expression levels in the patients that were resistant to chemotherapy were present at the time of diagnosis. If we can validate in additional patient samples that those microRNAs appear to be associated with this resistance phenotype, then we could structure a clinical trial to test new agents for those patients.

How many samples did you look at?

We were able to profile 34 samples and had enough RNA remaining to do PCR on 28 of those.

These were from people at various stages of the cancer's progression. Did the stage seem to matter when it came to identifying the microRNAs associated with chemo-resistance?

It didn't appear to be the case. In general, small-cell [lung cancer] is still divided into two classes: limited stage or extensive stage, which is metastatic and the only treatment is chemotherapy. More than two-thirds of patients are diagnosed with extensive stage up front, and only four of the patients in this group were limited stage. That didn't seem to matter with their response and outcome.

Is the plan now to get samples from a larger pool of patients?

The ultimate goal is to confirm [these findings] in an independent cohort. But one thing to point out is that, in general, small-cell [lung cancer] is treated with either chemotherapy or chemotherapy and radiation, depending on the stage. Because of that, there are usually very small amounts of tissue that are available; all that is done is, at diagnosis, a fine-needle aspirate or a core biopsy, and that's what we have to work with, as opposed to the other types of lung cancer where a majority of patients at the early stage have surgical resection, [providing] a lot more tissue to work with.

One of the issues [we faced] was just being able to get enough tissue out of paraffin-embedded samples to do the profiling and PCR.

Assuming you are able to confirm these microRNAs as biomarkers, how do you envision the findings being applied clinically?

If we are able to validate an independent cohort, we would PCR for those specific microRNAs that validate. That would require less tissue and, hopefully, a faster turnaround time to make a "yes or no" decision whether [a patient] is at risk for this de novo chemo-resistance.

The first clinical application would be to identify a drug that works in that situation and conduct a clinical trial where we stratify patients to the standard therapy versus the new therapy, and see whether the new therapy holds up and works in that situation.

Do you have a sense of how far something like that could be down the road?

The rate-limiting steps are getting samples for the independent validation, then confirming we have a drug we think would work in that group. Optimistically, I would say a year to two.

The other thing we're working on right now is to see whether these microRNAs are involved in the mechanism of resistance. That would then have therapeutic implications, too.

So you think that somehow antagonizing these microRNAs might potentially be used in conjunction with chemotherapy?

Right. And we're waiting for the first results of clinical trials with microRNA [drugs] in humans to come out so we can see the side effects of those therapies. Each microRNA may have its own set of side effects, so the first thing is to see what happens with the current studies.

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