Dr. Kopetz received the AACR-Waun Ki Hong Award in April. The American Association for Cancer Research (AACR) granted Dr. Kopetz this award to recognize his leadership in the development of novel therapies for patients with BRAF-mutated metastatic colon cancer with poor prognoses, according to a statement from the AACR.
Dr. Scott Kopetz
Using molecular profiling and patient-derived xenografts, Dr. Kopetz discovered resistance mechanisms and helped develop approaches to overcome such resistant pathways. His clinical studies analyzing vemurafenib, cetuximab, and irinotecan resulted in new additions to National Comprehensive Cancer Network guidelines and led to the FDA approval of encorafenib plus cetuximab for adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation after prior therapy.
In an interview, Dr. Kopetz shared his unique road to research, how his engineering background influences his work, and why his recent award’s namesake holds special significance to him.
What led to your medical career? Growing up, did you always want to be a doctor?
Dr. Kopetz: My interest initially was in engineering. I grew up in Tennessee from a family of engineers and doctors. In college, I completed a degree in biomedical engineering and electrical engineering.
I had the opportunity to spend one summer at the National Institutes of Health, where I did some research on the structure of the HIV integrase enzyme. It was fundamental basic research with some engineering overlay and required spending 4 days a week working in the dark in a laser lab to analyze the structure of this protein.
One day a week, I was at Georgetown in the HIV/AIDS Clinic, where I collected blood samples and saw HIV/AIDS patients. At the end of the summer, I reflected and realized that I really enjoyed that 1 day out of the week, much more than the other 4. I enjoyed working with patients and interacting with people and thought I’d enjoy the more direct way to help patients, so made a pivot into medicine.
Was the rest of your medical training more traditional?
Dr. Kopetz: My path was a little atypical for a physician scientist. I pursued a medical degree at Johns Hopkins, did internal medicine training at Duke, and then came down to MD Anderson Cancer Center [in Houston, Texas] to do a fellowship in medical oncology, and also obtained a PhD in cancer biology, where I explored mechanisms of resistance to colorectal cancer treatment.
While a traditional physician scientist typically obtains a PhD training in the middle of their medical school, I completed my medical training and then went back to get a PhD. It was a different, nontraditional route.
What is your current role, and what is most inspiring about your work?
Dr. Kopetz: I’ve been at MD Anderson now for 20 years in GI medical oncology. I recently stepped into a new role of helping facilitate translational research at the institution and am now Associate VP for translational research.
I’m excited about where we are in cancer research. I think we’re moving into an era where the amount of information that we can get out of patients and the rapidity in which we can move discoveries is much greater than it has ever been.
Our ability to extract information out of patient biopsies, surgical samples, or even minimally invasive techniques to sample the tumors, such as liquid biopsy, has provided tremendous insights into how tumors are evolving and adapting to therapies and [provides us] opportunities for novel interventions. This opens up ways where I think as a field, we can more readily accelerate our understanding of cancer.
The second component is seeing the rapidity in which we’re now able to execute ideas in the drug development space compared to years before. The pace of new drug development has increased and the innovations in the chemistries have opened up new opportunities and new targets that in the past were considered undruggable. For example, the mutated oncogene, KRAS, was once an extremely challenging therapeutic target and considered undruggable. Mutations in the p53 gene, a tumor suppressor gene, were similarly challenging. I think the convergence of these two trends are going to more rapidly accelerate the advances for our patients. I’m optimistic about the future.
Tell us more about the novel therapies for patients with BRAF-mutated metastatic colon cancer for which you were a lead researcher.
Dr. Kopetz: A lot of [my] work goes back over 10 years, where my [research colleagues and I] were targeting the BRAF V600E oncogene in colorectal cancer melanoma and identified that this worked well in melanoma but was relatively inactive in colorectal cancer despite the same drugs and the same mutations. This led to a recognition of optimal combination drugs that really blocked some of the adaptive feedback that we saw in colorectal cancer. This was a key recognition that these tumors, after you block one node of signaling, rapidly adapt and reactivate the signaling through alternate nodes. This finding really resonated with me with my engineering background, thinking about the networks, signaling networks, and the concepts of feedback regulation of complex systems.
The strategy of blocking the primary oncogene and then blocking the feedback mechanisms that the tumors were utilizing was adopted in colorectal cancer through this work. It took us 10 years to get to an FDA approval with this strategy, but it’s really encouraging that we’re now using this strategy and applying it to the new wave of KRAS inhibitors, where the exact same feedback pathway appears to be at play.
Does your engineering background impact your work today?
Dr. Kopetz: Yes, I’ve found that my engineering training has provided me with complementary skills that can significantly contribute to the development of innovative technologies, computational approaches, and interdisciplinary strategies for advancing cancer research.
Today, I do a lot of work understanding and recognizing complex networks of signaling, and it’s the same network theories that we learned and developed in engineering.
These same theories are now being applied to biology. For example, we are very interested in how tumors adapt over the longer term, over multiple lines of therapy, where there is both clonal selection and clonal evolution occurring with our various standard-of-care therapies. Our hope is that application of engineering principles can help uncover new vulnerabilities in cancer that weren’t evident when we were thinking about CRC as a static tumor.
