CONVERSATIONS WITH GIANTS IN MEDICINE

A conversation with Charles Sawyers

Charles Sawyers of Memorial Sloan Ket- ended up being a transformative experience. tering Cancer Center has defined the Joel Ernst was my attending when I molecular lesions that cause cancer and was a resident. I got to know him, and we used these insights to develop new drugs. just clicked. I was able to parlay roughly six Specifically, Sawyers (Figure 1) was one months of the third year of residency into of the critical members of the team that a research experience in his lab. I agreed brought imatinib and dasatinib to bear on to cover the medical ICU at night at San chronic myeloid leukemia (CML). Further- Francisco General Hospital while I worked more, his work has identified second-gen- in Joel’s lab during the day. It was a pretty eration antiandrogen drugs to treat castra- grueling night schedule, but it was totally tion-resistant prostate cancer. Watch the worth it to me: I got to have my cake and eat full interview on https://jci.org/videos/ it too. We were cloning genes involved in cgms to hear the personal stories of a phy- white blood cell phagocytosis of bacteria. sician-scientist called “the greatest cancer JCI: At what point did you turn towards researcher of our time” by one of his peers. hematology/oncology? JCI: Can you tell me a little about your Sawyers: Oncogenes were being upbringing? described, the Bishop/Varmus thesis was Sawyers: I grew up in Nashville, Tennes- starting to gather momentum, and I just see, the child of two physicians. My father knew that something big was here. I knew Figure 1. Charles Sawyers in New York City on was a surgeon and rose through the ranks at March 2, 2018. Image credit: Alexey Levchenko. it was what I wanted to do clinically when I Vanderbilt to be the chairman of surgery. My was on the leukemia service at Moffitt Hos- mother was an anesthesiologist. I had three pital [UCSF]. To frame the timing, this was uncles who were physicians and a grand- disease by physicians who had labs, and that when allogeneic bone marrow transplanta- father who was a physician. I tried to resist is when the spark was lit. I remember dif- tion was relatively new. CML was a disease becoming a physician a little bit. ferent lectures where I suddenly felt there in which bone marrow transplant was really I was a brainy kid and especially liked existed a whole world that I didn’t know starting to show exciting outcome data. math and science, but I also played compet- anything about that maybe I dismissed too I read all of the early papers from Now- itive tennis all through high school. I decid- early. I can remember a lecture on the struc- ell and Hungerford on the description of ed to head to Princeton for college because ture of hemoglobin and the understanding the Philadelphia chromosome (BCR-ABL). I wanted to spread my wings. I found that of the sickle-cell mutations, and the ability And then Janet Rowley’s discovery, through I really liked taking liberal arts classes to reduce a complex disease down to a point cytogenetic banding, that BCR-ABL result- and decided to major in history. I wasn’t mutation in one gene fascinated me. ed from a reciprocal translocation and the dead set on going to medical school, but I I was able to forgo many of the elec- further race to clone the translocation. Joel thought I probably would, so my strategy tives of the fourth year and spent a year pointed me to a paper from Owen Witte was, take the requirements as an “in case” in a pharmacology lab, getting exposure wherein he cloned the translocation and had and explore other things, and the history to experimental design. I met a new com- the first cDNA. I contacted Owen as a third- department at Princeton is outstanding. munity of postdocs and graduate students. year resident to see if I could do research I had the somewhat unique opportu- JCI: But at the same time, you weren’t in his lab. I had to get out a typewriter and nity, through my dad, to visit China in 1980. willing to give up medicine, heading west write a letter and put a stamp on the enve- Shortly after Nixon made a trip to China, it for a residency in internal medicine. lope and mail it. And he wrote me back and opened the gates and I was part of one of the Sawyers: I went to UCSF because my said, “Call me.” We were able to work it out early American trips and found it incredibly older cousin, who had also gone to Hopkins, so that I started in his lab before I started my interesting. It sparked an interest in public was a rheumatology fellow and working in a clinical fellowship. health and the way medicine is organized, basic immunology lab and he said, “You’ve The timing was very serendipitous with which was part of what I was initially inter- got to come out here. It’s unbelievable.” I the recent invention of PCR. Our question ested in when I started medical school. was avidly reading everything about molec- was, could you detect the BCR-ABL tran- JCI: At what point did you find the sci- ular medicine and there was, at that time, script by PCR? That was a pretty novel idea entific side of medicine? an incredible community of physicians who back then. Owen let me work through one Sawyers: In the second year of medical were MD-scientists at UCSF — Harold Var- of the technicians to keep the project going school at Hopkins, we were taught about mus and Mike Bishop — to name just two. It when I started in the clinic, knowing I would have all the connections and access to the samples from patients that would make this Reference information: J Clin Invest. 2018;128(4):1203–1204. https://doi.org/10.1172/JCI120979. story into something important. We pub-

jci.org Volume 128 Number 4 April 2018 1203 CONVERSATIONS WITH GIANTS IN MEDICINE The Journal of Clinical Investigation lished a nice paper showing you could track have anyone to call. So I actually called the to mine. This person needed some help, low levels of transcripts in patients who had patient, who lived in Santa Barbara — still and I was a young assistant professor, and had an allogeneic transplant. The prognos- does — and then I went to the airport. as I learned more about it, I got pretty inter- tic impact was not clear at that time, but now JCI: Did you have some champagne on ested in the idea of why hormone therapy it’s a standard test. the flight? works and why it stops working. I made a JCI: When did you meet Brian Druker? Sawyers: I had some champagne with conscious effort to go to meetings of other Sawyers: Early in my postdoc, Owen Brian and colleagues the next day. But one disease areas and try to gauge the status of trusted me enough to represent the lab at is only one, and it took a few more months the big questions in the fields. And prostate meetings. And Brian was in Tom Robert’s for the rest of the data to come in, and it cancer attracted me the most. group and then Jim Griffin’s group at the Far- was amazing. After we saw the clinical The first paper we published in pros- ber. We were basically at equivalent stages benefit in chronic-phase CML patients, tate cancer described a whole new set of and clicked because of our backgrounds; Bri- we opened the trial to patients with blast models, the equivalent of what we now an had also gotten an MD with no real prior crisis — a phase of the disease that is lethal call patient-derived xenografts, which we research experience until he was a postdoc. within months. It was incredible how many would grow in male mice, and then we We stayed close when we each got our jobs, patients who were near death’s door went would castrate the mouse and the tumor Brian at Oregon Health Sciences University. into a complete remission within a matter would regress and then regrow. These were Brian invited me as a guest speaker to of weeks of taking this pill. much better than the existing three cell OHSU in the early ‘90s and showed me JCI: Some of your patients relapsed. lines, two of which no longer expressed data with a compound [STI-571, later called Sawyers: Not only were they relapsing, the androgen receptor. It seems obvious imatinib mesylate/Gleevec] that Nick they relapsed very quickly. I felt like we had in retrospect that the androgen receptor Lydon and colleagues had sent him from to understand resistance as quickly as pos- must still be working in what’s now called Ciba-Geigy Pharmaceuticals [now Novar- sible; I was aware enough of the euphoria of castration-resistant disease. But it was not tis]. It looked pretty interesting, but it was success and the agony of defeat. I catalyzed a popular idea at the time, and no one was very hard at that stage to know if we should my lab group to make understanding resis- trying to develop better androgen-therapy put in a big effort. He asked me to help him tance the highest priority project. Mercedes drugs. The long and short of it is a project champion the idea, and that began a long, Gorre and Neil Shah were critical in discov- that was supposed to discover a multitude extremely fruitful collaboration. ering that resistance was caused by new of different resistance mechanisms ended JCI: What was it like as you were getting mutations in the BCR-ABL kinase domain. up pointing to the androgen receptor. the data from the dose-escalation trials? We got it right, but we oversimplified; we At the time we started this, I had devel- Sawyers: We didn’t want to get too sequenced 13 patients, and 11 of 13 had the oped a little bit of street cred in drug devel- ahead of ourselves in terms of excitement. same mutation, so we thought there was opment, having done imatinib and dasat- Like any phase I trial in cancer, it was a clas- only one resistance mechanism. But with inib, but I really didn’t know how to make a sic 3+3 dose escalation, where three patients more analysis and more patients, it quickly drug. I knew enough people to talk to phar- receive the initial starting (very low) dose, became clear that there were numerous ma, but to them, this was such a yesterday and nothing happened. There was actually a mutations that could all confer resistance. idea and everyone had moved on to kinase hint at the next dose level that one patient’s In a stroke of good timing, John Kuri- inhibitors. At one point, we just said, we white blood cell count seemed to get better. yan’s lab had just solved the first ABL crys- had to do it ourselves. I worked with UCLA At the next dose level, all three patients had tal structure. We decided to share data chemist Michael Jung and a postdoctoral a decline in their white blood cell count. and had people from our groups meet to fellow, Samedi Ouk, and we had a well- The real test of true benefit in CML is review data. We went up to see them and designed cell-based screen where we knew to test the bone marrow for the presence mapped out all the mutations using the exactly the activity profile that a compound of BCR-ABL. Those results started coming software that they had to view structures. that could solve this had to have, because in after patients had been on active doses It became clear that the mutations were the drug that existed at the time called for six months. I was lucky enough to have changing the conformational flexibility of bicalutamide could be overcome by over- the first patient who had a complete cytoge- the kinase. Imatinib is very special in how it expressing the androgen receptor. It seems netic remission. I remember this because I binds ABL: ABL has to be in a conformation simple now, but we just recreated that con- was in my office on a Saturday morning get- that’s completely inactive, which it flips in text, made a high-throughput screening ting ready later that day to fly to a meeting and out of for a microsecond. What a lot of platform, and out came enzalutamide. in Europe, where Brian and I were going to the new mutations did was prevent it from JCI: If you couldn’t be a physician or discuss the first clinical data with Novartis. being so flexible. The idea was to find an a scientist, what do you think could have Back then, we would get the results from inhibitor that could tolerate other confor- captivated you all these years? the cytogenetic analysis on the fax machine. mations, and dasatinib is that drug. Sawyers: I feel like I’m an academic at My fax machine started whirring, and there JCI: During this time, you had also heart. I would’ve probably been a journal was this report that showed 0 out of 20, turned your attention to prostate cancer. editor, as I love reading — I love writing. I and I could not believe it. I called the lab to Sawyers: The prostate decision was like just talking about ideas. make sure, and then I called Brian, but he influenced by a number of variables. One had already left for the airport, so I didn’t was, there was a urologist’s lab right next Ushma S. Neill

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