Cancer researcher named first STAT Biomedical Innovation Award winner – STAT

Dr. Charles Sawyers work over a 34-year career not only led to the development of the blockbuster drug Gleevec for chronic myelogenous leukemia, but to a better understanding of a concept thats now fundamental to oncology that cancers can overcome powerful drugs to develop resistance. And in a rare example, Sawyers role in creating the prostate cancer drug Xtandi was not born within industry, but from within the halls of academia.

And for those milestones, Sawyers, a Howard Hughes Medical Institute investigator and chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, was just named the first-ever winner of the STAT Biomedical Innovation Award. The award is presented to a top researcher in biomedicine whose work has helped to define their field and, in the process, helped patients. He will accept the honor at the inaugural STAT Summit on Thursday in Cambridge, Mass.

Sawyers wasnt always interested in medicine, though both his parents were physicians, nor did he originally have an eye toward cancer treatments. Still, he did make his way to medical school at Johns Hopkins. He vividly recalled how a lecture on the structure of hemoglobin in the context of sickle cell disease helped him gain an appreciation for how detailed knowledge of a disease and its underpinnings which is what his current field of precision medicine celebrates could yield clues for how to solve therapeutic challenges. It was unbelievably cool, he said.

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And it was the drama of taking care of patients with chronic myelogenous leukemia and curiosity about why certain treatments worked well against the disease that led Sawyers to wonder more about new options. But ultimately, he wanted in on the action. The genetic abnormality that is symptomatic of CML was cloned around the time he was finishing his medical training, and remembered thinking, God, I want to be in the middle of this, he said.

STAT spoke with Sawyers about some of the highlights of his career and broader issues he sees in science. This interview has been condensed and lightly edited.

We hear a lot about how discoveries are often curiosity-driven is that what led to Gleevec?

For me, it was curiosity about why you get leukemia, [and] how does this translocation cause leukemia once it was found.

It was in the early 90s. I was at the University of California, Los Angeles, and had my own lab. BCR-ABL [which is a mutation found in almost all CML patients] is in the cytoplasm of cells and a monoclonal antibody approach [which others were trying] was not even on the table. Youd have to use a small molecule. And the challenge was to make a drug that would be safe.

But that argument had kept a lot of people from doing a deep dive [into CML]. Kind of out of the blue, this group had this small [enzyme inhibitor] program for two or three main targets. One of these seemed to also inhibit [BCR-ABL enzymes] and that became Gleevec. We didnt understand why at the time.

How did you realize Gleevec was going to be a cancer drug?

Seeing patients blood counts come down [as part of a Phase 1 trial] was incredibly gratifying, but we could do that with oral chemotherapy. The dose at which we start to see their blood counts drop matched exactly with lab studies we were doing on their blood cells. The scientist part of me was excited because we were doing exactly what we predicted.

The real amazing result was several months later when we did a bone marrow test to see if the BCR-ABL clone is shrinking in the tumor. I was taking care of a patient whose bone marrow test at six months after taking Gleevec showed zero [of the incriminating chromosome]. I was in my office on a Saturday morning, and this fax comes in, and Im like, Holy cow! I cant get a hold of anybody else in the trial, and so I just called the patient!

But that wasnt the end of the Gleevec story. What happened next?

What later happened is that patients can develop resistance and very quickly. And we figured out the reason. We found resistance in the regions of BCR-ABL where the drug was binding, but it didnt interfere with the [enzyme] activity, so it could still cause leukemia.

That led to all this amazing work and second-generation versions of the drug. That experience told me that if you have a cancer that responds well to a drug but then develops resistance, you need to absolutely understand the molecular basis of resistance with great precision and then you can overcome.

How was the Xtandi experience different than the Gleevec story?

We realized after Gleevec that we needed to go after the androgen receptor [in prostate cancer] in a more aggressive way. But companies we approached were moving away to focus on [work with enzymes].

Thankfully, I had a chemistry partner at UCLA named Mike Jung, who got interested in helping us with this. The big difference is that we found Xtandi in our labs at UCLA with chemistry screening and measuring biological activity. The clinical development I had nothing to do with.

What were the lessons you learned from both those drug discovery processes?

Youve got to know the disease and really have a molecular understanding of the disease and the drug target and how the tumor corresponds to the drug target. Its really about precision science.

The other is persistence and passion. Theres lots of reasons that you could talk yourself out of why its not going to work. Obviously, if its not working, you dont continue.

Stepping back, what has been the most surprising thing in oncology?

I think the benefit from immuno-oncology has been greater than expected. The fact that tumors that have complex genetic alterations can have a dependency on a single driver, to me, is amazing. So, this idea to me that there is a house of cards, and theres a card at the bottom that causes the whole house to collapse that, to me, is probably one of the most unexpected and fundamental insights from this work.

Anything youre disappointed by anything you thought wed have figured out by now?

Were going way too slowly with figuring out combination therapies. I think there are way more excuses, and I find that disappointing. Theres a lot of business development issues because the therapies for combinations are often at different companies. Companies often make their own drugs or buy out other companies [and that slows things down].

A second issue is that its a given that theres going to be more toxicity when you give more than a single agent. Weve shot ourselves in the foot a little bit by adopting this a once-a-day-therapy as the only kind of therapy we put forth for clinical development. Were not willing to accept the old chemotherapy mindset where we give four or five drugs at once, and cause incredibly toxicity for three- to six-month period and then stop treatment. I think we should readdress those kinds of concepts, again, with targeted therapy.

Cancer drugs are among the most expensive, and since you have experience developing them, is that something on your radar?

Its not on the radar on the discovery and development side. One thing I think about and try to project to my trainees is that were problem-solvers and we want to find solutions that can help patients. We think about the cause of whatever were trying to solve, the underlying science, and how we get to do something feasible therapeutically. Question of cost of the drug doesnt really enter into the discussion at all.

But the issue of price is in the zeitgeist and I serve as a director at Novartis (NVS), so Im very aware of [drug pricing] from the company perspective and as a human being who cares about patients having access to drugs it concerns me deeply.

What do you see as big challenges facing science as a whole and the future of the trainees in your lab?

Im optimistic about the ability to solve some of these important medical problems within and outside cancer. I think the science is so compelling that the investment as a country weve made in basic science over 30-plus years has really laid the foundation to make an impact. What I find distressing one is, with our current administration in the White House and this anti-science attitude. Fortunately, budgets have been maintained despite threats to cut them, but they certainly havent grown in any significant way. And I think were losing opportunities to further expand our expertise as a country in leading the way in biomedical research.

As far as the trainees, I feel like sometimes I have to be a cheerleader because the payline for grants are terrible. But theres just nothing like this as a career. Its the joy of trying to solve a complicated problem, but the impact of that is enormously gratifying if patients benefit.

Now were seeing more attention to some of the other issues that influence science, like implicit bias and a diverse workforce. How have you seen them change over the course of your career and how are you thinking about them now?

The conversations about this in any sector of work were almost nonexistent 30 years ago or so.

My lab? Racially [its] not diverse. [In terms of] gender, theres lots of diversity. Among early-career researchers, gender diversity is rich, but later on [there are fewer women because] its the usual things, like childbearing, [that causes them to leave].

I play some role in helping shape that. The lack of diversity, though, is very concerning to me, with African Americans in particular. Its very difficult to convince young minorities to take this delayed gratification approach, where you really dont get your first full-time job until youre in your 30s, and you may not get your first [major research] grant until youre in your mid-40s. Thats not a great advertisement for someone who doesnt have a lot of great role models [in the field] to begin with. Its kind of a Catch-22: We dont have enough diversity in our senior faculty to inspire younger minorities to come into this career path.

Its a gradual process, unfortunately [to change these things].

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Cancer researcher named first STAT Biomedical Innovation Award winner - STAT