Researchers use DNA origami to generate tiny mechanical devices that deliver a drug that cuts off the blood supply to tumors in mice.
Charles Sawyers, who began his research career just as the genetic details of human oncogenes were emerging, codeveloped Gleevec, the quintessential targeted cancer therapy.
April 1, 2015|
DR. C SAWYERS 14/RUBENSTEIN/WIKIMEDIA COMMONSEven before beginning a clinical fellowship at the University of California, Los Angeles (UCLA), in 1988, Charles Sawyers already had an intense interest in chronic myeloid leukemia (CML). In the late ’80s, allogeneic bone-marrow transplants were a cutting-edge therapy that gave CML patients a chance at a cure. Sawyers had cared for a patient with chronic-phase CML. “He was my own age, a fireman,” recalls Sawyers. After the transplant, the patient developed graft-versus-host disease and died. “That had a profound impact on me—to watch someone with a lethal disease, who was feeling fine and probably would have survived for 5 years with standard therapy, make the decision to undergo a potentially curative therapy and die from its toxicity. ‘There has to be a better way,’ I thought.”
Sawyers had moved to UCLA so he could work in Owen Witte’s laboratory on the molecular determinants of CML. Witte was the first to clone the BCR-ABL oncogene, a fusion gene created by a translocation that gives rise to the Philadelphia chromosome, now known to be responsible for CML. “It was incredibly exciting to now have demonstrations that cancer can be caused by a single genetic event,” says Sawyers, who received both his clinical and research training at a turning point in oncology—when laboratory studies on the molecular biology of cancer began to merge with clinical care. “The whole cancer field was asking whether these oncogenes were really capable of causing cancer in an experimental model.”
“I would like to see every patient’s tumor genotyped to guide treatment decision making . . . even if there are not currently therapies to target certain mutations.”
Here, the clinician-scientist talks about his experience in the operating room right after high school, how he migrated toward laboratory research, and his role in developing two highly successful targeted cancer therapies.
A medical family. Sawyers grew up in Nashville, Tennessee, surrounded by physicians. His mother was an anesthesiologist, and his father and two uncles were surgeons. He did well in high school and thought about going into medicine. “But at that point, I just wanted to go to college and get out of Nashville.”
Surgeon’s assistant. For two consecutive summers starting after his senior high school year, Sawyers worked as a scrub technician at the hospital where his mother was on staff. “That was an important experience,” he says. “It made me not want to be a surgeon! The techniques were fascinating and this affirmed my interest in human biology, but—and this is going to sound terrible to surgeons—I didn’t find it intellectually inspiring.”
Barefoot medicine. At Princeton University, Sawyers majored in history, focusing on the history of science. He wrote his senior thesis on how medical education changed in China in the 20th century, from the pre-Communist era, when there was investment in Western-style medicine, to a new generation of health-care workers, known as “barefoot doctors,” who delivered basic medical care in rural areas after Mao Zedong came to power. In 1980, after his junior year, Sawyers experienced the phenomenon firsthand when he traveled to China with his father, who had been invited to give lectures and meet with clinicians because of his expertise in stomach surgery. “I remember seeing very traditional medicine practiced. It was really eye-opening,” he says.
Playing catch-up. After college, in 1981, Sawyers entered medical school at Johns Hopkins University in Baltimore. “I was not the typical premed biochemistry major who had worked in a lab in college. As soon as medical school started, I realized I was way behind in knowledge of fundamental biology compared to my classmates. I thought, ‘Wow, everyone around me has already had this material.’ That first year of medical school was miserable.”
A new sense of self. By his second year, Sawyers had caught up academically. “I began to rethink my worldview of medical science and became much more interested in research.” Sawyers says he was also inspired by physician lecturers who approached a clinical issue by dissecting it down to the molecular level. “The hemoglobin gene mutation that causes sickle cell anemia had been defined, and a hematologist who taught us had collaborated with a structural biologist to solve the crystal structure of the protein that explained the disease. That was mind-blowing—to understand the medical disease at that level of detail.”
“I knew I was a late bloomer scientifically, but I wanted to give it a real solid try to become a physician-scientist.”
Going west. After medical school, Sawyers went to the University of California, San Francisco (UCSF) for a residency in internal medicine. “Molecular technologies had allowed people to ask disease-focused questions in a new way. This was a powerful tool to dig deeper, and I saw that happening in all kinds of ways on the UCSF campus.”
Leukemia calling. “I knew very early on that oncology was what I wanted to do because of the combination of science that was breaking, especially the concept of oncogenes. At UCSF, one of my early rotations was on the leukemia service. Everyone said this was the worst rotation because you work your butt off and the patients are dying, which is, of course, depressing. But I found it to be exhilarating. It was super intensive medicine, and many of the patients I took care of were my own age. Emotionally, it’s extreme and draws you in.”
Resident to researcher. While Sawyers was at UCSF, Witte published his study on the Philadelphia chromosome. Witte had also been to medical school, where he had caught the research bug early and never pursued clinical training. “Witte told me that he usually didn’t take MDs but that he would be interested in speaking to me. After the interview, he offered me a spot in the lab,” says Sawyers, who ended up spending five years there. “It was more than enough time to get me where I needed to be, scientifically. After two years, I felt I was on a postdoc level, and the final year prepared me to start my own lab.”
Molecular detection. While in Witte’s lab, Sawyers demonstrated that you could molecularly detect the BCR-ABL fusion transcript in the blood of CML patients who have relapsed after a bone marrow transplant, and that this molecular marker appears before cytogenetic signs of relapse, the standard way pathologists measured tumor growth. “The PCR technique had just come out when I joined the lab. I was at the right place at the right time to optimize the PCR conditions and use clinical samples to analyze the levels of BCR-ABL mRNA.” Sawyers also showed that the MYC transcription factor together with BCR-ABL can transform a normal cell into a malignant one. He also showed that the primary function of the normal ABL protein, a tyrosine kinase located primarily in the nucleus, is to negatively regulate cell growth.
A lab of his own. “At this point I knew I had the right stuff for a lab-based career. I had no hesitation; I was totally immersed.” In 1993, Sawyers accepted an assistant professorship at UCLA, moving just 50 yards from his postdoctoral lab into UCLA’s new cancer center. “When I first joined the Witte lab, the question was whether this oncogene causes cancer. Then, the question had become ‘How?’ We were working on the signal-transduction pathways of what happens in the cell downstream of BCR-ABL.” Sawyers’s laboratory identified two independent signaling pathways activated by the BCR-ABL oncogene and showed that the Jun kinase, activated by BCR-ABL, is required for transformation by the oncogene. Although busy with research, Sawyers kept one foot in the clinic, spending 20 percent of his time as an attending CML physician.
A drug for CML. During a 1995 visit by Sawyers to Brian Druker’s Oregon Health and Science University lab, Druker showed him data on a tyrosine kinase inhibitor, imatinib, that selectively killed leukemia cells expressing BCR-ABL. Druker and Sawyers worked to convince Switzerland-based pharmaceutical company Ciba-Geigy, which had discovered the compound, to test it in CML patients. Sawyers, Druker, and Moshe Talpaz, a hematologist then at MD Anderson Cancer Center in Houston, were the investigators responsible for the first human clinical trial of imatinib, now approved by the US Food and Drug Administration (FDA) as Gleevec. The trial began in 1998, two years after Ciba-Geigy had merged with Sandoz to become Novartis. The team used the PCR assay Sawyers had developed to detect BCR-ABL in patient samples. Other than bone marrow transplantation, which was only available to a minority of patients, therapies for CML had infrequently led to a reduction in the percentage of CML cells in the bone marrow, and complete remissions were rare.
“One of my patients was the first to have a complete remission, and others soon followed. That’s when we knew this was a game changer,” says Sawyers.
From relapse to response. Sawyers and colleagues tested imatinib not just on chronic-phase CML patients, but on very advanced blast-crisis CML patients who had only a few months of life expectancy. “We thought, ethically, we should offer this to these patients, and amazingly, even some blast-crisis patients went into remission, which was incredible. These patients are often in wheelchairs and can require oxygen. Within a week, some were like new people.”
But the responses were short-lived. Finding out why patients relapsed after therapy became the most important question in the world for him, says Sawyers. Using patients’ samples, his lab showed that resistance was due to new mutations within the BCR-ABL kinase domain that interfered with drug binding. Sawyers’ work benefited from research by John Kuriyan’s group at Rockefeller University identifying the crystal structure of the BCR-ABL protein. “This was one of the most exciting periods of my life, realizing we can totally understand how this drug is causing resistance.” Sawyers proposed a way to overcome resistance, describing a theoretical new compound at the 2002 American Association for Cancer Research annual meeting. A few days later, he received a phone call from a scientist at Bristol-Myers Squibb (BMS) who had heard his talk. It turned out that BMS had a compound with the characteristics Sawyers had described. Sawyers’s laboratory showed that this compound, which eventually became dasatinib (Sprycel)—approved by the FDA for treatment of CML in 2006—can overcome resistance to imatinib. And Sawyers again partnered with Talpaz to lead the clinical trial that showed dasatinib worked in imatinib-resistant patients.
A new direction. In 2005, Sawyers received an invitation from Harold Varmus, then president of Memorial Sloan Kettering Cancer Center, to head a new research program that would capitalize on using genomics data to analyze tumors and identify new cancer drug targets. “I thought it would be an amazing opportunity. With my experience with Gleevec, I had a sense of where the field could go. Seeing how you could get a tumor to shrink well, even though you are poking it in just one spot, was really eye-opening, and generated great optimism in my mind to go after complex solid tumors. I knew there were Achilles heels that had to be there, because I had seen it firsthand.”
Beyond CML. While still at UCLA, Sawyers had begun to work on prostate cancer. “I wanted to branch out and began thinking that hormone therapy for prostate cancer was a similar question to what we were asking with CML,” he says. From seven different mouse models, Sawyers’s lab got the same answer—that prostate tumors resistant to hormonal therapy expressed much higher levels of the androgen receptor. Knocking down the androgen receptor using a genetic trick called RNA interference restored sensitivity to hormone therapy. “It was quite parallel to what we had seen with the kinase inhibitors—that despite genetic complexity, tumors tend to fall back on the original driving oncogenic event to escape targeted therapy.” Sawyers collaborated with synthetic chemist Michael Jung to develop a new antiandrogen therapy for prostate cancer. The compound, enzalutamide (Xtandi), was licensed by biopharmaceutical company Medivation and is now approved by the FDA for treatment of advanced prostate cancer.
Genomic sequencing. “I would like to see every patient’s tumor genotyped to guide treatment decision making. I think that information is going to be useful, even if there are not currently therapies to target certain mutations. It’s such a compelling question that the cancer centers with the resources are just doing it themselves.”
Cancer drug costs. “I don’t think it’s justified to charge some of the amounts being charged for incremental benefit, but for really dramatic benefit, I do think it can be justified. I don’t know what the right price is, but companies need incentives to recover their research and development expenses. There is an inability of the US Medicare system to negotiate drug prices with pharmaceutical companies, whereas in other countries there are intense negotiations to prove the value of a new drug in economic terms. I think it’s clear that the tide is pushing in that direction.”