Sawyers' Scientific Approach Paved Way for Discoveries in Two Tumor Types

Charles L. Sawyers, MD

During his undergraduate years at Princeton University, Charles L. Sawyers, MD, studied history. Now, well into his career as a physician and translational scientist, Sawyers is busy making it. Currently chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center and a Howard Hughes Medical Institute investigator, he has played a seminal role in the discovery of three groundbreaking cancer drugs. And in developing these drugs, he has helped to create an approach to the treatment of cancer that has transformed cancer research.

Although Sawyers’ most recent discovery concerns his work in developing enzalutamide (Xtandi), a drug therapy for the treatment of patients with metastatic castrationresistant prostate cancer (mCRPC), he applied many of the same scientific methods he developed while working with leukemia earlier in his research career. Sawyers, over the course of his career, had explored how signaling pathway aberrations in cancer cells could be exploited as targets for new drugs. In his work with enzalutamide, Sawyers focused on how prostate cancer cells develop resistance to drugs that target the androgen receptor (AR) pathway. To appreciate and understand his approach to solving scientific problems, one has to go back to when Sawyers began his career, first as an undergraduate, then as a medical student, and, finally, as a physician scientist.

History Provides a Lesson in Research

Sawyers was born and raised in Nashville, Tennessee, into a family of physicians: a grandfather, father, two uncles—all surgeons—and a mother, an anesthesiologist. As a young student, he excelled in mathematics and science, so one would have thought that a career in science, especially medicine, was inevitable. Yet, when he headed off to Princeton University for his undergraduate education, those areas of study were far from his mind. Instead, he chose to major in history. A liberal arts education, he felt, would broaden and enrich his outlook on life. Ultimately, he said, it contributed to his ability to isolate and analyze science problems.

“It exposed me to a certain style of research. You select a topic, investigate and master a body of evidence using original sources, and come up with a conclusion. You grab onto something you think is controversial or fascinating in some way, and try to get to the heart of it,” he said. “I actually think that that’s what research in science is all about, and frankly, that’s how a liberal arts education works.”

It was during this time that he encountered the work of science historian Thomas S. Kuhn, PhD. Kuhn, through his magisterial work, The Structure of Scientific Revolutions, argues that scientific progress is the result not so much of an evolution in ideas, but rather a revolution in ideas—one led by “intellectual mutineers,” insurgents who overthrow one conceptual worldview or paradigm to replace it with another; thus, Galileo and Copernicus upended astronomy, Newton rewrote physics, and Darwin revolutionized biology. The idea that new discoveries in science could result not from the logical extension of older ideas but from an overturning of those ideas was intriguing to the young Sawyers, and ignited his interest in and passion for the scientific method that has informed his life’s work.

Learning to Be a Scientist

After graduating from Princeton, Sawyers enrolled in Johns Hopkins University School of Medicine in Baltimore. “Hopkins had an outstanding faculty made up of people who were involved both in teaching medical students and running a laboratory, combining research with clinical activity,” he said. At Hopkins, Sawyers was greatly impressed and influenced by Donald S. Coffey, PhD, a faculty member and researcher who worked on prostate cancer. “He is a man of great personal charm and charisma, with a renegade spirit that I greatly admire,” said Sawyers. Coffey, according to Sawyers, also has a unique talent: to get students genuinely interested in a problem, to get them to dig into it, and to get them excited about biomedical science.

“It was inspiring. And don’t forget, this was a time when the tools of molecular biology were just being broadly applied to questions in medicine. The ability to understand the genetics of a disease was leading to fascinating new insights,” said Sawyers. “Cancer was a fascinating challenge. A lot of the features of biomedical science are part of cancer research, so you’re pretty much in the mainstream of all research. You can draw on many different lines of investigation. Solving problems that arose from the research was incredibly interesting. The real question was whether I could stomach the clinical part of it.”

That question, it appears, was answered during his residency at the University of California, San Francisco (UCSF), when Sawyers began a monthlong rotation through the leukemia ward, caring for patients with cancer, including many who were around his own age. “It was an incredibly rewarding month for me. Of course, there were sad moments. But the relationships with the patients and the families were incredibly driving and rewarding. I knew right then that that’s what I wanted to do. It wasn’t something that I could have predicted, that I’d have thought I’d have felt so strongly about in advance. But it just grabbed me.”

Sawyers’ interest in chronic myeloid leukemia (CML) ultimately led him to sign up for postdoctoral research in molecular biology at a lab led by Owen N. Witte, MD, at the University of California, Los Angeles (UCLA). Sawyers credits Witte with teaching him how to be a scientist. “He taught me scientific rigor, how to think like a scientist. Whenever I went to him with a problem, he’d say, ‘Boil that down to a question you can test.’”

At the time Sawyers joined the UCLA lab, the group was concentrating on the Philadelphia chromosome, a mutant that is formed when pieces of two separate genes, BCR and ABL, break off and then rejoin to form the fusion oncogene bcr-abl. He worked on elucidating how bcrabl triggers a cascade of intracellular signaling that ultimately leads to CML. In the recesses of his mind, Sawyers tucked away an idea: Perhaps a therapeutic strategy might emerge from an understanding of bcr-abl activity, one that could be applied to other cancers as well?

Interestingly enough, it was his work here that, although not quite as disruptive of old ways as Kuhn had described, would ultimately transform cancer research and challenge and overturn established ideas on how to treat it. These new ways of thinking about cancer and cancer treatment resulted in groundbreaking approaches, at first derided by critics, but then increasingly adopted by the cancer research community.

A New Age in Cancer Treatment Begins

While Sawyers was studying how bcr-abl signaling triggered cancer in blood cells, and trying to determine how abnormalities in the signaling pathways could be exploited as targets for new cancer therapies, physician scientist Brian J. Druker, MD, of Oregon Health & Science University, along with Ciba-Geigy (now Novartis) chemist Nicholas B. Lydon, PhD, were attempting to devise a completely new type of treatment strategy. They were looking for a drug that could disturb the signaling pathways driven by bcr-abl, and thereby frustrate the culprit’s ability to incite the deadly proliferation of cancer cells, but at the same time leave normal cells untouched.

The concept that such a drug might be efficacious against CML gained few immediate adherents. The objections of the proponents of conventional wisdom multiplied and concerns were raised: What if the drug that obstructed bcr-abl activity also injured other cellular components critical to life?

Just as Sawyers would later not be dissuaded by critics of his approach to prostate cancer treatment, Druker and Lydon proceeded despite these objections. As they expected, imatinib first killed cancer cell lines that needed bcr-abl to grow while sparing normal cells, then killed cancer cells taken from patients with CML without harming unaffected cells.

The results of their groundbreaking work are now the stuff of medical history. Gleevec (imatinib) was soon hailed as a miracle drug. A new age in cancer treatment—that of molecular targeted therapy—had begun. As these new strategies were being devised, Sawyers would make good use of these new tactics later in his career, when his research began to focus on prostate cancer.

Overcoming Obstacles

But progress is never simple… there are always obstacles to overcome. “The sad part was that many patients in the later stages of CML developed resistance and relapsed quickly. We eventually would learn that some patients treated in the early stage relapsed as well, and that CML cells were still present at low levels in patients in remission. So we set out to solve the puzzle of why some patients were developing resistance,” said Sawyers, explaining what led him to begin investigating treatments for prostate cancer.

In collaboration with two of his trainees, Mercedes Gorre, PhD, and Neil Shah, MD, PhD, Sawyers identified the causes of resistance to imatinib. “It was the work of structural biologist John Kuriyan, PhD, that showed us how imatinib bound to bcr-abl. That work helped us understand how mutations could prevent the drug’s binding. Soon after that we found dasatinib (Sprycel), a new drug that inhibited bcr-abl in its mutated form.” Sawyers’ efforts in CML would equip him to go on and try to conquer the next disease that caught his attention. “The work defined a path that has now been pursued again and again with other cancers,” he said. “I applied the same strategy myself in developing a treatment for metastatic prostate cancer.”

Keeping Resistance in Focus

Current thinking on the development of treatment resistance in prostate cancer holds that a patient relapses because the ARs on the tumor cells are no longer driving the disease. Sawyers, always one to challenge conventional wisdom with an eye toward overturning it, felt otherwise. “We thought that mutations in the androgen receptor might be the cause,” he said.

DR SAWYERS’ SELECTED PUBLICATIONS:

• Balbas MD, Evans MJ, Hosfield DJ, et al. Overcoming mutationbased resistance to antiandrogens with rational drug design. eLife. 2013; 2:e00499. Published April 9, 2013.
• Glickman MS, Sawyers CL. Converting cancer therapies into cures: lessons from infectious diseases. Cell. 2012;148(6):1089-1098.
• Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTENdeficient prostate cancer. Cancer Cell. 2011;19(5):575-586.
• Chi P, Chen Y, Zhang L, et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010; 467(7317):849-853.
• Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324(5928):787-790.
• Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinibresistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006; 354(24):2531-2541.
• Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305(5682):399-401.
• Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002; 2(2):117-125.
• Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-880.
• Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344(14):1031-1037.

As it turned out, he was right. Cancer cells, he discovered, mutate and then go on to produce an abundance of ARs, which once again fire up the cell’s signaling activity to rob a drug of its efficacy. He knew from experience that what would be needed was a drug that could suppress the uprising of deviant signaling activity, shut down the mutinous ARs, and inactivate them.

In collaboration with UCLA biochemist Michael E. Jung, PhD, Sawyers and his team screened for and found a compound that was successful in shrinking drug-resistant tumors in mice. But would it work in patients with prostate cancer? Indeed it did. The drug that eventually emerged was enzalutamide.

On August 31, 2012, the FDA approved enzalutamide for the treatment of patients with mCRPC. The approval was based on a single randomized, placebo-controlled, multicenter trial involving 1200 patients.

An old hand at ferreting out cancer’s tricks, Sawyers is already one step ahead of his enemy and planning his next move against the disease’s ability to circumvent its own annihilation. “We’ve already started thinking about resistance to enzalutamide; we started before we even saw it happen in patients. We knew it would eventually become a problem. We’ve seen it happen with other targeted therapies.”

On a Mission to Speed Up Combination Therapy

Sawyers’ pet project now is to persuade both the FDA (which he considers sympathetic), and the business community to get behind combination therapy with these drugs. Right now, he argues, we are doing exactly what was done 70 years ago in infectious disease. “We give one drug, it works, and then it stops working. Then we give the next drug, it works for a while, then it stops working,” he said. “Isn’t it blatantly obvious that we need to give these drugs in combination?”

No one, he says, will argue that we shouldn’t give combination therapy. “What I find somewhat amazing is that we’re not doing it fast enough, we’re not embracing it. It’s sort of my mission right now to advocate for that. I’m pushing on all fronts.”