A Conversation with Yariv Houvras, M.D., Ph.D.

A Conversation with Yariv Houvras, M.D., Ph.D.

EIPM Member Yariv Houvras, M.D., Ph.D. is an internationally-renowned expert in the treatment and care of patients with advanced thyroid cancers, including differentiated thyroid cancer, papillary and follicular cancers, poorly differentiated, anaplastic and medullary thyroid cancers.

Since joining the faculty at Weill Cornell Medical College in 2011 he has been particularly interested in cancer genetics in order to identify personalized therapies to fight cancer based on the genetic profiles of an individual’s tumors.  He also directs a cancer genetics lab at Weill Cornell Medicine where he uses a model organism, zebrafish, to identify new drugs and drug targets.

We hope you enjoy learning more about Dr. Houvras’ work and research interests.

 

Can you tell our readers a little more about your research interests?

In my clinical practice as a medical oncologist I take care of patients with thyroid cancer. I’m particularly interested in the use of targeted therapies for patients with thyroid cancer. I’ve been doing this for about ten years, and as I’ve cared for these patients what I’ve realized is that we have a lot of limitations.

For too many of my patients, we’re unable to match a drug for their specific tumor. This has inspired me to try and address some of these problems in the laboratory. In the lab we use zebrafish as a model organism, they have a number of attributes that make them a very powerful tool for biomedical research.

I realized that by working with the Englander Institute for Precision Medicine, we could better understand the mutations that occur in patients, and then create those mutations in the fish in order to build a model of the thyroid cancer to identify new drugs for patient treatment.

Do zebrafish offer distinct biomedical research benefits over other models, like organoids, which are used fairly extensively at the Englander Institute?

There are similarities and differences. When we do manipulations in zebrafish, we are introducing a genetic mutation found in a human into the fish. These fish possess most of the same organs and tissues as humans; including a thyroid, for example. So we’re going to create a thyroid cancer in a fish that harbors the same mutation that the human patient harbors, and we’ll study what happens. We’re not introducing human cells into the fish, that’s a common misunderstanding. We’re using a whole organism approach to build genetic models. For endocrine organs this may be important as the thyroid responds to hormonal signals from the hypothalmus and pituitary.

Can you tell me about the clinical trials with TKI that you’re involved with?

Many of my patients with thyroid cancer have genetic mutations that allow us to match a specific kinase inhibitor with a patient. For example, there are patients that have BRAF mutations that respond very well to a combination of BRAF and MEK inhibitors. We don’t fully understand why some patients respond better than others, or when the medicines stop working what the mechanisms of resistance are.  We have also seen that patients with mutations and rearrangements in the RET gene are also very sensitive to treatment with RET TKIs, but unfortunately these treatments are also associated with the development of drug resistance.

We’re trying to understand why these medicines aren’t curative for these patients. And we’re using zebrafish models to probe those questions.

When did you become interested in identifying personalized therapies to fight cancer based on the genetic profiles of an individual’s tumor?

I became a medical oncologist around the same time as the first targeted therapies for cancer were being proven to be clinical useful. These targeted therapies include Gleevec for chronic myelogenous leukemia (CML), and the EGRF inhibitors for lung cancer.

These were really formative examples, we saw patients with CML being cured by taking a pill. We hoped this was the beginning of the end of more common cancers, that we’d be able to find the driver mutations and match them with kinase inhibitors, and cure these diseases. But in the majority of cases these small molecule kinase inhibitors are disease-controlling but not curative. As we started to get more experience using these medications in thyroid cancer, I started to think that we needed to focus on why resistance occurs, and how we can understand the mechanisms of that resistance and design better therapeutic strategies.

What excites you about your work?

There are two big things. On the science-side, I love the creativity of discovery. We use CRISPR-Cas9 and genome editing technologies to read and write the genome like you would in a Word document. We can literally go into the genome and make any change we want: we can introduce foreign DNA, we can make changes that look exactly like what we see in human cancers. And that’s something we’ve only had the capability of using in this organism for about two years. And it’s something my lab is really on the vanguard of pushing forward.

I’m also really excited about using these technologies to address important medical problems, like exploring the limitations of kinase inhibitors in thyroid cancer or understanding how steroid hormone biosynthesis works. For example, we’re also working to identify new drugs for some very rare endocrine cancers that affect the adrenal gland in humans. The tools we’re developing for zebrafish really have tremendous promise for attacking the very important medical problems that we see in the clinic.

Where do you see your research moving in the short and long-term?

That’s a good question. In the next 3-5 years the challenge will be to identify specific genetic targets that we can then bring to the clinic. For example, I believe that our work with zebrafish in understanding resistance to kinase inhibitors in thyroid cancer is leading to the identification of specific targets to help design the next clinical trial. For example, we might combine two drugs that will work much better than either one alone because it will bypass this resistance mechanism.

In the longer term, working with genome editing and drug discovery to be at the vanguard where the model really starts to shine. What we’ve seen in the past 15 years of cancer biology and genetics using zebrafish is tremendous growth. We went from just a few labs working in this space to more than 100 labs globally, with a lot of collaborations and cooperation between them, and a lot of new models. That’s exciting!

How would you characterize your collaborations with the Englander Institute? 

The Englander Institute has been an essential partner in providing us with the most technologically advanced approaches to study human cancers from our patients. We have capabilities that exceed almost any institution in the United States. I have treated patients in my clinic using extensive molecular profiling, organoids, xenografts into immunocompromised mice, and very advanced genomic analyses of their tumors. This represents a suite of approaches that is just unparalleled. I feel very fortunate to have access to my amazing colleagues at the Englander Institute to work with.

I remain very committed to advancing the technological capabilities of zebrafish genetics for the benefit of human patients with cancer. When people come into our facilities and see first-hand what were capable of doing with zebrafish, it literally is mind-blowing. These capabilities hold tremendous promise for our patients. I’m really fortunate to have collaborators like those at the Englander Institute and the support of Cornell for these endeavors. Cornell has been uniquely supportive of our work.

What do you like to do when you’re not working?

That’s a good question. I do a lot of photography, I’m a very visual person. And I’m a runner, I’m training for my second New York City Marathon this fall.

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