As an oncology surgeon-scientist, Sonia Cohen, MD, PhD, has spent most of the last decade in clinical training. Nine years of surgical training and a fellowship in complex general surgical oncology left her little room for bench research – even though she knew that would eventually be part of her career path.

When it came time to obtain independent funding to start her own lab, our 2022  KL2/CMeRIT award was there to smooth the transition. The program provides two years of protected time for early-career clinician-scientists to pursue a research project of their choosing.

Cohen, an instructor in surgery and assistant in surgical oncology at Mass General Brigham (MGB), chose one of the hottest areas of genomic science: epigenetics. Her research focuses on understanding how changes in the structure and regulation of the genome give rise to cancer, with an eye toward developing prognostic tools and novel therapeutics based on new discoveries.

What is the specific knowledge gap that your K12/CMeRIT project seeks to inform?

The focus of my K12 is to understand how disruptions in the epigenetic regulation of cells give rise to cancer, and how that confers vulnerability to certain types of therapy, including oncolytic viruses.

Currently, only one oncolytic virus is FDA-approved, a herpes-based virus used to treat melanoma. It was developed empirically where, over time, people recognized that this virus could preferentially infect and destroy melanoma cells and other cancers. But the mechanisms by which that happens are really poorly understood.

Part of what allows cancer cells to survive is that something has gone awry in the immune cells’ ability to recognize and destroy a cancerous cell before it proliferates. Cancer cells take advantage of that. Yet that same vulnerability can enable a virus to destroy the cancer cell. We’re trying to understand that interplay.

Oncolytic viruses are a little bit like the ugly stepchild to cancer immunotherapy. They came into clinical use around the same time, so they haven’t received as much attention. Now, as we understand more about the role of the immune system in cancer surveillance and how cancer vaccines work in combination with the immune system, we can start to think about how to use oncolytic viruses to activate the immune system to attack cancer.

Your work as a surgeon-scientist encompasses both treating cancer patients and investigating the mechanisms that lead to cancer. How do those integrate in practice?

As a cancer surgeon, much of what I do is work in a multidisciplinary team to figure out how best to treat patients with cancer. My clinical focus is cutaneous oncology and sarcomas, and fortunately, we have effective tools for these cancers, so surgery is just one part of treatment.

“What excites me about epigenetics is that it’s uncharted territory. That’s true even for normal cells but especially when it comes to how cancers develop and how we might modulate that with targeted therapies.”

In both my clinical practice and research program, the goal is to tailor a patient’s therapy to exactly what they and their tumor need. If I can use surgery to help them, in combination with some other tools, I will. Otherwise, my job is to figure out when surgery is not appropriate.

In terms of the research, we need to understand who would benefit from therapies we have and who might need new approaches. Understanding how these cancers develop and who has a higher-risk or lower-risk cancer in terms of spreading or recurring allows us to tailor therapy to the specific needs of each patient to limit the risks.

What motivates you to pursue this line of research?

One of the first labs I worked in was focused on transcriptional control of cell development. That got me interested in the idea that every cell’s job is to receive signals–from the environment, from other cells, from hormones or other biochemical messengers–and then modulate its response via transcriptional programs. In cancer, that system breaks down.

I started my graduate work in Mike Greenberg’s lab at Harvard Medical School studying pathways related to DNA methylation in neurons. At that time, genes were largely thought of as these very stable inherited marks, and epigenetic factors allowed for some degree of regulation as the cell developed.

What we understand now is that the organization of the genome is actually much more dynamic than was historically appreciated. Epigenetics opens up a whole other level of regulation within the cell that we can target.

What excites me about epigenetics is that it’s uncharted territory. That’s true even for normal cells but especially when it comes to how cancers develop and how we might modulate that with targeted therapies.

You have not been heavily involved in bench research since you got your PhD almost a decade ago. What’s it been like to get back into the laboratory?

I did my PhD as part of an MD/PhD program prior to finishing medical school. After that I did five years of surgical residency, followed by two years of surgical oncology fellowship. That’s a total of nine years of clinical training with no real opportunity for time dedicated to bench work for more than a month or two over the summer.

The K12 career-development funding has been critical to having protected time to build my research program, start my lab, and transition to independent funding. It would be much harder to do this without that opportunity.

“The K12 career-development funding has been critical to having protected time to build my research program, start my lab, and transition to independent funding.”

I can’t overstate what an opportunity a program like this is for someone at the career stage I’m at, trying to move toward independence. It’s geared toward providing clinicians in translational science the opportunity, support, and resources to take the next step, all within the context of a peer group. We’re not pure basic scientists, and we’re not pure clinicians; we’re kind of a separate population trying to do something a little bit different. We’re a little weird in that sense; we don’t really fit anywhere.

What I like about being a clinician-scientist is that my clinical life and my science life are integrated. I get to see patients every day. I see the cancer up close. It’s been amazing to be able to think about translating what I’m seeing in the clinic to the science I’m doing every day and how that can ultimately help the patients I’m caring for. It’s what I’ve been working toward for the past 40 years or so.

What will be your next step after this K12 ends?

One of the great opportunities this has awarded me is to set up my independent lab space. During this funding period, I moved into my own laboratory space at Mass General Brigham (MGB) in the Jackson 9 translational labs.

So now, as I’m finishing up experiments and writing up the project funded by the K12, I’m also training members of my own lab to carry out experiments and move forward with the science.

In our translational lab, we have the great opportunity to use patient samples to test some of the hypotheses that come from these more basic experiments. My office is directly above the MGB operating room, and we have a wonderful group of people dedicated to taking tumor samples from patients with a broad spectrum of cancer types. We bring the samples up to the lab and run a number of different assays to test our scientific hypotheses directly in our patients’ tumor samples.

Going forward in my own lab, I’ll be taking some of these basic mechanisms that we’re interested in and really trying to translate them into therapies for our patients.