As a physician-scientist in pediatric oncology, Adam Durbin, MD, PhD, has taken on the worst of the worst: recurrent treatment-resistant childhood cancers. His goal is to unlock the molecular code that flips a cancer cell from treatable with chemotherapy to stubbornly resistant.

Motivated by the children he treats in his clinical practice at St. Jude Children’s Research Hospital in Memphis, Durbin is on a roll. His lab has published back-to-back papers in Nature Communications and he was just awarded his first R01 as independent PI, in perfect step with the wrap-up of a five-year career-development grant.

Durbin says his current lab work was sparked in part by participating in Models of Disease (MoD) Boot Camp in 2016, when he was just starting his postdoctoral fellowship. We caught up with him the week his grant and latest paper were accepted to talk about his research aims, his motivation, and how MoD fit into it all.

Your new NIH-funded work will take a fresh look at treatment-resistant pediatric cancers. What’s your focus?

Classically, people have thought about cancer and resistance to therapy as being driven by mutations: As you treat a cancer, different genes may mutate that allow it to become resistant to therapies. If the cancer then comes back it doesn’t necessarily respond in the same way to the same therapies.

But in certain pediatric cancers, recurrent disease is not always associated with new mutations. We think something else is going on.

An evolving literature now suggests that cells can exist in different states driven by their transcriptome and controlled not by the genome but by the epigenome, a set of instructions that tells your cell what genes to turn on and what genes to turn off.

We have shown that in neuroblastoma, a very high-risk pediatric solid tumor that I treat clinically, cells exist in different states that can be either more sensitive to chemotherapy or more resistant. When treated, the cells may hide in the resistant state.

It’s been very hard to study this because it happens so quickly. You essentially have to kill the cells and study them in one state or another; you can’t study the dynamics. Since coming to St. Jude, I’ve collaborated with a number of investigators here to develop a set of tools to study these processes using fluorescent markers.

Using these tools, we are able to identify which cells are resistant to chemotherapy so we can separate them out and find out what makes them tick. We can watch cells become resistant to chemotherapy in real time under the microscope. Can we disrupt or reverse that process, to turn a chemo-resistant cell–the kind we think may cause relapse–into a chemo-sensitive cell that can be treated? That’s one of our many goals.

You’re seeing the worst of the worst of pediatric cancers. Why did you choose this field?

First, because I think pediatrics is great. The kids are really inspirational. They drive everything that we do. If you put all childhood cancers together, we do pretty well. In fact, we cure the majority of our patients.

“If we can cure a four-year-old diagnosed with neuroblastoma or a 14-year-old with osteosarcoma, we’ve given back an entire life. That’s an amazing thing to be part of.”

Looking long-term, for many diseases, the types of issues we now think about in pediatric oncology are related to the late effects of treatment, and how to reduce the amount of chemotherapy but still maintain good cure rates. That’s a key challenge. We know these therapies have multi-system side effects, and we’d like to prevent those. Of course our clinical treatments don’t work well in many other diseases, which is another challenge.

It’s actually very uplifting work. And yes, completely heartbreaking at times. So much more research is needed. The exciting part is finding something new – a new target, a new approach – which could generate new treatments. If we can cure a four-year-old diagnosed with neuroblastoma or a 14-year-old with osteosarcoma, we’ve given back an entire life. That’s an amazing thing to be part of.

Why did you want to become a physician-scientist?

As an undergrad in Toronto, I had a summer job in a cardiovascular research lab, and I just fell in love with molecular biology and genetics. I could see myself making scientific research a career, because of feeling like it could make a significant difference for people. But I also thought it would be really cool to care for patients and have those interpersonal connections that being a medical doctor provided.

When it was time to pick a path, I didn’t know which way to go. So I went to my mentor from those several summers of research for advice.

“I don’t know what to do,” I said. “I’ve got to pick one, right?” And he said: “Why not just do both?”

So I just did both. At the time, it was a very easy decision to make. And now I’m running my own lab and seeing patients, doing what I set out to do 20 years ago.

Looking back, how did the MoD course in 2016 fit into your career and training?

“Many of the concepts that I learned about in Models of Disease have really lasted. It sparked some of the work we did in my postdoc, which led to a next step and the next step after that.”

The course came at a very important time point for me, because I was right on the cusp of going from a purely clinical practice to really trying to focus and develop my postdoc research.

The training in the Models of Disease course is really very broad; it exposes you to a ton of different concepts and topics. That’s where things really germinate, right? You might be focused on pediatric oncology, but you hear about something going on in a completely different field or model system, or a different approach, and it sparks an idea. You start asking how to apply that to what you’re doing.

Many of the concepts that I learned about in Models of Disease have really lasted. It sparked some of the work we did in my postdoc, which led to a next step and the next step after that. I never would have predicted that we would be doing what we’re doing now, when I was taking the course.

So your MoD experience really shaped, at some level, your research track – very cool. As a young investigator in that clinic-to-lab transitional stage, what stood out for you?

It can be so hard to know what’s next at that stage. You’re coming out of this clinical environment that’s fairly structured. For many folks, how could you possibly know what you want to do? You might know which field you want to work in, but how can you get a sense of the full breadth of what’s going on around you? The MoD course works hard to give people a sense of the breadth of science. It helps people make connections.

Part of it was also just seeing people being fearless and hearing what you need to do as a clinician-scientist. Asking us: What is the most important question you can answer? The most clinically relevant? The most fundamental biological question? Whatever that is, take that and run with it. Really try to answer that question.

For me, the question has been: What drives these super-malignant pediatric cancers? And how can we disrupt that in a way that’s minimally toxic and maximally beneficial? Much of that was inspired by the Models of Disease course. It’s been really cool to build on that base.

I still talk with several folks who were in my MoD class. We trade grant drafts and manuscripts to get each other’s opinions. I’m getting feedback on whether they think something is really a big problem or if we’re answering a question properly. It’s a whole community of people who aren’t directly in my field, specialists in cardiology or endocrinology or genetics. It’s great.