Interrogating Cancer Cells: A Conversation With鈥�

The cofounder of Foghorn Therapeutics studies how defects in gene traffic control lead to a variety of cancers and other diseases.

Listen to the podcast interview with Cigall Kadoch and Jason Pontin by clicking the orange button on the player above.

Cigall Kadoch, the cofounder of Foghorn Therapeutics, is one of the stars of Flagship鈥檚 ecosystem. In 2013, while still a graduate student at Stanford University, she discovered an overlooked link between defects in a chromatin remodeling complex (which unspools the tightly coiled DNA in our cells to allow the information in genes to become accessible and form mRNA and protein products) and a variety of human cancers.

At the time, Kadoch was completing her graduate training in the laboratory of the pioneering chromatin researcher , where she studied a chromatin regulatory complex known as BAF. She observed that nearly all cases of the childhood cancer synovial sarcoma can be linked to a genetic mutation in one of the BAF proteins. Kadoch was able to halt the rampant growth of synovial sarcoma cells by forcing BAF to eject the mutant protein. In 2015, she discussed her findings with 蘑菇视频APP managing partner Doug Cole, who suggested creating a company that would develop an entire range of therapeutics for cancers and other diseases caused by altered chromatin function. Together, Cole, Kadoch, and Crabtree founded Foghorn Therapeutics, in 2016.

Originally known as FL38, Foghorn is developing ^TM , a broad platform of proprietary techniques that target diseases with genetically determined dependencies in the chromatin regulatory system. Foghorn scientists isolate, purify, and characterize chromatin remodeling complexes (CRCs) to reveal mutations in component proteins that are directly implicated in specific conditions. By linking these disease-causing mutations to defined patient populations, the company is translating biological insights into a rich and diverse drug development pipeline. 鈥淎s we鈥檝e applied this approach, it has revealed multiple unprecedented mechanisms of developing cancer,鈥� explains Doug Cole. 鈥淭hese insights have opened up very promising strategies to create drugs to correct these defects.鈥�

Today, is an assistant professor in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute and Harvard Medical School and an institute member and the co-director of the Epigenomics Program at the Broad Institute of MIT and Harvard. Flagship senior advisor Jason Pontin spoke to Kadoch at Flagship鈥檚 offices in November 2019.

Jason Pontin: What drew you to the life sciences?

Cigall Kadoch: My early inspirations in science, and particularly for cancer research, came from personal experiences. I had a close family friend, who took care of my sister and me when we were young, pass away very quickly from metastatic breast cancer. This took a real toll on me, especially in my developing, adolescent years, and it further drove my interest in science that she had helped to cultivate, along with my parents. While always very interested in science, I became dedicated to the idea of using science to understand and treat disease, even from a young age. It doesn't usually mean much for a 12-year-old to say, 鈥淚'm going to focus my career in cancer research, and I'm going to be a scientist.鈥� But somehow it really did travel with me all this way.

JP: Were mentors important to your development?

CK: I was raised just outside of San Francisco, in Marin County. As a high school student, I was fortunate to take an advanced class called biomedical science taught by a remarkable teacher, Mr. Skip Lovelady. He was incredibly innovative in his approach to teaching science. High-school students in his course would not only learn but use methods often taught only at the graduate school level鈥攁 unique exposure to state-of-the-art techniques. Mr. Lovelady attended my wedding this summer, and he told me he鈥檚 still showing his students the latest science: they're doing CRISPR now; they're doing base editing, etc.

鈥淭he combination of the sequencing studies and our discovery about the mechanism behind a rare cancer was a shot heard around the world.鈥�

Mr. Lovelady鈥檚 class had such an impact on me because I was suddenly empowered to have scientific conversations with my uncle, Dr. Richard Matthews, working here in Boston: an MD-PhD and a clinician in radiation oncology. I went to Boston for an entire three-month summer, seeing patients with him and getting exposure to Harvard Medical School and the entire Boston-Cambridge ecosystem before it was what it is today. I would go with my uncle to his clinic every day, watching some patients getting better from radiation therapy and others passing away right before my eyes. And that really hit me. I couldn't explain why some people didn鈥檛 get better鈥擨 mean, the real molecular underpinnings鈥攁nd I wanted to understand what underlies disease in the first place and what drives resistance to therapies.

And so my subsequent education focused heavily on molecular biology and on cancer. I ended up doing all my scientific training in the Bay Area. I went to the University of California, Berkeley, for my undergraduate studies in molecular and cell biology, did research at UCSF at the medical center at Parnassus in hematology and oncology, and went on to the Stanford School of Medicine to do my PhD in cancer biology.

JP: How did your education lead to the focus of your lab: chromatin regulation and, in particular, chromatin remodeling?

CK: When I entered Stanford, I was intensely wedded to cancer research because of these personal experiences. I really didn't want to do anything other than cancer research. When I was interviewing, I met , who would become my graduate school mentor. At the time, I didn't think that his lab would be right for me, because it didn't focus on cancer at all. Crabtree is a world-renowned developmental biologist, a Howard Hughes investigator, and a long-time member of the . He鈥檚 an unbelievable scientist, but his lab was much more focused in neurobiology and stem cell biology, with essentially no focus on cancer.

When I first talked to Crabtree, his whole lab was focused on chromatin organization and its involvement in the development of the vertebrate nervous system. But he piqued my interest by telling me that the lab had found some changes in a protein complex (the same one we now study) that were responsible for dictating cell fate. A postdoc in the lab had discovered that subtle changes in the subunit composition of this chromatin complex gave rise to neural progenitors becoming postmitotic neurons or not. Playing with these switches could direct cell-fate transitions. For me, that was interesting because of course cancer is almost always developmental processes gone wrong鈥攁berrantly hijacked, if you will.

While I was committed to joining a cancer research lab, I couldn't get it out of my head that these developmental processes, for all we could guess, might be involved in cancer. So, intrigued by the rigor of the science, I joined Jerry's lab, and I told him I only wanted to study cancer. He said, 鈥淥kay, well, we don't have anybody doing that. Here鈥檚 your bench, here are your pipettes, knock yourself out.鈥� I remember thinking, Why he would ever believe in me, this new kid? I hadn't had any exposure to biochemistry. But he allowed me to figure out my own way. One of the ways that we were able to connect the chromatin remodeling complex to cancer was to ask, Do we fully know what is actually bound to this complex? What is the nature of the complex in mammalian cells? And that was really Jerry's sweet spot, because these remodeling machines had been studied extensively in yeast and maybe a little bit in Drosophila; but it was Jerry who was really the one who started to study chromatin remodeling in mammalian cells and even in mouse models鈥攁gain, mostly in the context of development.

One day, looking through a long list of proteins that had been identified to bind to the chromatin complex, I found a protein called SS18 that meant absolutely nothing to me at the time. But using a simple search, I found that SS18 had been linked uniformly to a highly aggressive, rare cancer called synovial sarcoma, in which 100 percent of patients have the exact same chromosomal translocation鈥攁nd that exact same chromosomal translocation, in every single known case, fuses 78 amino acids of another protein called SSX to SS18, resulting in the SS18-SSX fusion oncoprotein. So, if SS18 were indeed a true part of this chromatin remodeling complex, it would offer us a unique opportunity to understand what happens when that remodeling complex is perturbed.

I proceeded to biochemically interrogate cancer cells isolated from the tumors of individuals with synovial sarcoma, and develop systems to address whether or not this fusion oncoprotein was indeed tethered to the chromatin regulatory complex. And there was my much-sought-after link between cancer and this chromatin remodeling complex! We went on to figure out the mechanism (at least a big part of it鈥攚e have done much more since, here in Boston) and this resulted in in 2013.

JP: But hold on, how did you know you鈥檇 not just discovered some curiosity: a one-off mechanism?

CK: That was the question. Was this a mechanism that might be applied to just this one rare cancer? Or, could we use these insights to shed light on other human cancers and even diseases besides cancer? It turned out the timing was perfect, because as we were asking this exact question. A flood of studies rolled in from the first big wave of exome sequencing studies in human cancer. There was a period of two weeks I'll never forget, when I was sitting at my at my desk at Stanford and I could not keep up trying to print all the articles that were coming out almost on a daily basis in all the best journals, linking mutations in the genes encoding the various components of this regulatory system to cancer. I remember getting up multiple times to trek to Jerry's office at the very end of the hall, saying, 鈥淥h my God, again!鈥濃€攜ou know, another paper linking this exact regulatory process; in fact this exact protein complex鈥� with cancer. This was, for us and for the field at-large, entirely unexpected.

鈥淚 tell my students that when one hypothesis is incorrect, it is easy to consider it as a failure, but we can also see it as a new opportunity for another, perhaps more interesting path.鈥�

As we started to do the simple math, we found that if we tallied the frequencies of the mutations in all the different components of this complex (called the BAF complex), they would add up to over 20 percent of human cancers. That鈥檚 a huge burden of disease. It wasn鈥檛 what Jerry or anyone thought would be the results of sequencing studies, because for years these complexes were thought to be rather uninteresting, to say the least. We thought that they would just play maintenance roles in the cell, and hence be terrible drug targets鈥攖hat they were just maintaining the structure of the genome and playing homeostatic roles. Now we know that these complexes play critical roles in cell type differentiation and that different perturbations are present in different cancer types, many of which are now known to actually be the cause of the cancer. The combination of the sequencing studies and our discovery about the mechanism behind a rare cancer was a shot heard around the world.

And that was the foundation for the early ideas for what would ultimately form my young lab. I was fortunate to connect with people here in Boston; and I was recruited to start my lab right out of grad school, researching chromatin regulation in health and disease. These ideas formed some of the basis for Foghorn Therapeutics as well: investigating a system that is present and active in every one of our trillions of cells, in different ways. It turns out that defects in this particular process are very frequent in both cancer as well as other disorders such as intellectual disability and autism spectrum-like syndromes.

JP: How did Flagship convince you to start up a commercial venture at the same time that you were building your first academic lab? Either would seem enough to occupy your full attention.

CK: There are now 25 people in my lab at Dana-Farber and Harvard Medical School, but in the winter of 2014, when I was just moving across the country from California, it was just me. I had a number of ideas that I knew would be the most pressing questions to try to answer in the field. Chromatin regulatory complexes had not been known to play such critical roles in disease development. Now we knew that bare fact, but we didn鈥檛 understand the structural nature of these processes or the biochemical principles that regulated their assembly or their function. In the context of mammalian human cell chromatin, that was what I perceived as a major barrier to progress in the field, if we were going to be able to do something for this very large percentage of human cancer patients that have these exact mutations in their tumors.

I was fortunate to gain early support from the NIH and from a number of foundations to get a lab off the ground and to pursue these academic questions. But I was still very eager to see how far we could translate the mechanism we had discovered, and the many more we were on our way to discovering, into meaningful therapeutics. I quickly realized it was going to be challenging to do everything. That鈥檚 a trap otherwise excellent scientists fall into: they end up not being able to push any one area to the level of depth and rigor we wanted for our new lab. If one is going to have a clear scientific identity and be really good in one area, it's best to stay very focused on that area. I thought that our lab could have more of an impact in the field if we focused on the biology, because it's the biology that's going to drive the impact and be the basis for new therapeutics.

To translate new biological insights into therapeutics, I realized we needed a company if we weren鈥檛 going to partner with large pharmaceuticals from the get-go. That鈥檚 why I decided to found and develop Foghorn. Chromatin regulation was a very exciting new area to explore. But I knew that it was also a challenging area and that we had a number of questions to answer. And I knew answering those questions would take intensely dedicated people, who were not diluted across different areas of biology and who were entrepreneurial and creative in their thinking. So I decided on a small, focused company that would have the possibility to expand to a wide range of diseases, if we did it right.

JP: How did you meet Doug Cole who has been your cofounder in building Foghorn?

CK: I'll never forget my first meeting with Doug at the old Flagship offices. I knew nothing about venture capital, I knew nothing about company-building, I had no prepared pitch, and I wouldn't have considered myself an entrepreneur. I was really just a scientist with an idea and the goal to make an impact in a new area of medicine. I knew this was the opportune time to begin something with an exciting vision. But I had no plan. I sat with Doug and proceeded to tell him what we had done and what my vision was for the future. We both say that within five minutes of talking with one another and realizing that we had complementary sets of expertise and thinking about science, we knew that we'd be great partners and we wanted to create a company together. It wasn't long after that that Foghorn was established.

JP: Why was it necessary to create Foghorn to develop medicines that address altered chromatin function? Why couldn鈥檛 a large pharmaceutical company do the work? Or, a university?

CK: That is a great question. I am an early investigator. My perception was that it would be hard in the academic setting of a lab to translate an understanding of these complexes into medicines. But I was equally hard pressed to see how a large pharma company, which has many different areas to tend to, would ever do the work. In a pharmaceutical company, one investigator is often covering multiple programs. I didn鈥檛 see how that would work in an area as complex as chromatin regulation. The other issue was that our first foray into this entire area of chromatin regulation was focused on a very rare disease, which big pharma would just shelve. I wanted to use the insights from these rare diseases to inform much larger therapeutic opportunities as well. And it was the insights we gained from synovial sarcoma that have informed the large number of other programs at Foghorn. These are major opportunities with a large number of patients in cancer, as well as other indications. Put another way, mechanistic insights come from groups fully focused on one area. And then insights give rise to new thinking about therapeutic targets as well as the actual chemistry behind getting small molecules or other types of agents to these proteins in the nucleus.

"Biology is like a dense and complex forest and it is up to us how to use our compass and identify clues along the way that tell us if we are going in the right direction."

JP: Do you think cancers will be broadly understood in our lifetime? And if they are broadly understandable, will they be cured鈥攐r, is cancer just part of the trip if we live so long?

CK: I think that we are making great progress toward understanding all cancers, especially with the sequencing efforts that I've described. Those sequencing insights may have sent us back to square one, but it鈥檚 a very important square one: the correct square one. Human genome sequencing鈥攊n particular, exome sequencing from human tumors鈥攈as shed light on where to place our emphasis in terms of therapeutic development. I think that what this has also taught us is that there is unlikely to be one 鈥渃ure鈥� to cancer or one therapeutic that is effective across all cancers. There aren鈥檛 enough unifying features. However, there are areas, or clusters, that might respond well to specific inhibitors, often beyond the initial indication the therapeutic agent was developed to target. The biotechnology industry will treat genetically defined diseases with genetically defined therapeutics. That鈥檚 going to be a major approach going forward.

JP: As a scientist, you've been lucky鈥攁t least, you鈥檝e been prepared for good luck. Is failure also an important part of the process?

CK: I prefer to look at it as rerouting. I tell my students that when one hypothesis is incorrect, it is easy to consider it as a failure, but we can also see it as a new opportunity for another, perhaps more interesting path. I mean, there have been times where my lab has gone down every single possible experimental path because we were convinced a hypothesis was going to be correct. And no matter what experiment we did, the science was telling us to look another way. So I think the most important thing is being able to recognize those signs early and often. Biology is like a dense and complex forest and it is up to us how to use our compass and identify clues along the way that tell us we are going in the right direction. That lesson comes in part from experience but also just in thinking about things evolutionarily. Because evolution makes sense. I don't often use the word "failure," but we fail every day, and sometimes happily so, because failure has routed us to a new area we would never have even explored had we not accumulated important negative data.

JP: said, 鈥�.鈥� What problems do you want to solve in the next five to 10 years?鈥�

CK: I hope we can achieve a full understanding or a much more complete understanding of the various disease-relevant gene regulatory mechanisms that are governed by these chromatin regulatory complexes and, on the flip side, more ways by which such complexes can be perturbed.

JP: You are very confident that mechanistic explanations are possible. Do you ever worry that biology may be too complex for mechanistic explanations that humans can understand? I mean, do we need mechanistic explanations to treat disease?

CK: I think we need mechanistic explanations for a large number of diseases. This rule isn't without exceptions. There are therapeutic targets that have been identified and are known to be important鈥攆or specific cancer types鈥攚here we still don't fully understand the mechanism. We work backwards in these cases. For example, we know that if you deplete or target certain proteins in certain cancers, then those tumors regress. That provides pretty strong support for going after that therapeutic target, but the specific molecular mechanism sometimes remains unknown. But in every case in our lab where we've discovered a mechanistic explanation, we have also unmasked new therapeutic opportunities. So mechanistic pursuits are, in a way, the gift that keeps on giving, because it both propels basic research forward and suggests new medicines.

Editor's note: This conversation has been edited for length and clarity.

Story By

Jason Pontin

Jason Pontin is a senior advisor to 蘑菇视频APP, where he contributes to guiding the enterprise鈥檚 thought-leadership and publishing, in addition to advising its companies. From 2004 to 2017, Jason was CEO, editor-in-chief, and publisher of鈥�

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