Profile of Charles L. Sawyers

PROFILE Profile of Charles L. Sawyers harles Sawyers is a rock star in his Ras, a handful of research teams across own right. Last year, Sawyers, the country were hot on the trail of other Cchair of the Human Oncology oncogenes. Witte focused on the Phila- and Pathogenesis Program at delphia Chromosome, a genetic aberra- Memorial Sloan–Kettering Cancer Center tion that juxtaposes two genes, dubbed and a member of the National Academy BCR and ABL, when human chromo- of Sciences, posed with singer Debbie somes 9 and 22 swap segments, producing Harry of the rock band Blondie to pro- a hybrid enzyme in blood cells that jams mote cancer research in a campaign the cells’ growth restraints and leads to sponsored by the Geoffrey Beene Cancer CML. Patients with CML have a pro- Research Center. The unlikely assemblage fusion of frenetically dividing white blood of rock star and researcher shined the cells. Left unchecked, the disease can kill spotlight on pioneering efforts in trans- within 3 years of diagnosis. “This was an lational cancer research. Few physicians example of a cancer where the genetic deserve that spotlight more than Sawyers, abnormality was clear. That’s what at- who co-discovered the targeted cancer tracted me to Owen’s lab,” says Sawyers, drug, Gleevec, forging a path to cancer who joined the laboratory as a post- treatment that has now become increas- doctoral fellow in 1989. That move was ingly common. merely the opening act to a career punc- Born to physicians who served as a tuated by startling revelations, fruitful source of inspiration, Sawyers grew up in partnerships, life-saving discoveries, and a Nashville, Tennessee household where even heart-wrenching disappointments. medicine was the order of the day. A After 4 years of fundamental research standout in school, Sawyers excelled in on the biology of CML, Sawyers accepted science and mathematics. However, he an assistant professorship at UCLA’s headed toward college without the con- Charles L. Sawyers. Department of Medicine in 1993. Thanks, viction that his professional path was pre- in part, to a 1995 physician-scientist destined. “Although I was heavily exposed award from the National Cancer Institute, to medicine through my parents, my un- biology, which he realized would forge the Sawyers continued to study how BCR- cles, and my grandfather—all physicians, future of medicine. “My cousin pointed ABL signaling sent blood cells cascading I never felt like I was part of a lineage,” out mentors at UCSF with the patience toward cancer. Meanwhile, researchers he says. So, when it came time to choose to take on a smart kid with no elbow elsewhere were on the hunt for drugs to a field of study at college, Sawyers decided grease,” Sawyers says. One of those treat CML. Among them were two re- that the humanities could help widen mentors, infectious disease biologist Joel searchers whose names are now immor- his worldview. He majored in history at Ernst, now a professor of medicine at talized in the annals of cancer research: Princeton University, focusing on the his- New York University’s Langone Medical Oregon Health and Science University tory of science. At Princeton, Sawyers’ Center, became Sawyers’ partner in a molecular biologist Brian Druker and interest in the scientific method was 6-month-long stint performing molecular Ciba–Geigy (now Novartis) biochemist sparked by the writings of legendary sci- cloning experiments. To continue the Nicholas Lydon. Druker and Lydon hit ence historian Thomas Kuhn, whose apprenticeship, Sawyers decided to look upon a strategy to achieve what cancer storied opus, The Structure of Scientific for a postdoctoral position in molecular researchers had long sought: attacking Revolutions, has inspired generations of biology. During the early 1980s, California cancer cells while sparing normal cells. researchers pursuing science. was a hotbed of discoveries in biology, Using a tack that transformed cancer Sawyers’ scientifictemperamenttook and, in some ways, its epicenter was San treatment, the duo sought to disrupt the shape when, in 1981, he enrolled in the Francisco, then home to researchers like signaling pathways driven by BCR-ABL Johns Hopkins School of Medicine. There, Harold Varmus and Michael Bishop, who with a drug that could thwart the mutant Sawyers attended lectures in molecular bi- went on to unearth Nobel Prize-winning enzyme’s ability to spur cancer; normal ology with the eagerness of a budding findings in molecular oncology. cells, which lack the mutant enzyme, they physician intrigued by basic science. “When The laboratory Sawyers chose was reasoned, would be left unharmed. Logi- I learned that the clinical presentation of headed by University of California, Los cally appealing, the idea was not without some diseases could be narrowed down to Angeles (UCLA) molecular biologist its shortcomings; skeptics denounced single-nucleotide mutations, I was awe- Owen Witte, who discovered a leukemia- the attempt as misguided mostly because struck,” he says. Awe gave way to passion as causing protein produced by the fusion they believed other genetic flaws might Sawyers pored over volumes of basic bi- of a viral gene with a mouse gene; the also drive CML. Further, the skeptics ology literature, soon surpassing peers who human version of the protein is now well- decried, a drug that disrupted BCR-ABL had undergraduate degrees in science. To- known for its central role in triggering might harm any of the other dozens of ward the end of medical school, his cousin, a rare form of blood cancer called chronic similar life-sustaining cellular enzymes. a physician, recommended Sawyers move myeloid leukemia (CML) in people. “I However, the duo was not to be dis- across the country to complete his medical had taken care of patients with CML suaded. In 1996, they reported that a drug residency at the University of California during my medical studies, so the possi- called imatinib, now marketed as in San Francisco (USCF). bility of performing research on CML captivated me,” Sawyers says. In the wake California Calling of Massachusetts Institute of Technology ’ This is a Profile of a recently elected member of the Na- Sawyers arrived in California determined molecular biologist Robert Weinberg s tional Academy of Sciences to accompany the member’s to gain laboratory experience in molecular discovery of the first human oncogene, Inaugural Article on page 16759 in issue 39 of volume 107. www.pnas.org/cgi/doi/10.1073/pnas.1107215108 PNAS Early Edition | 1of3 Downloaded by guest on September 27, 2021 Gleevec, killed an experimental cancer enzyme to turn on pathways that kept the Freedom-to-Explore award from Bristol– cell line that needed BCR-ABL to grow cells in overdrive (2). Before long, Saw- Myers Squibb that allowed Sawyers to in laboratory dishes, although largely yer’s trainee Neil Shah had found more pursue risky high-stakes research. “Also, sparing other cancer cells that depended than a dozen such resistance-conferring I wanted to work on a disease that was on a different enzyme for their growth. mutations in the enzyme, making it near fairly common in the population, unlike The finding held when tested on normal impossible to design drugs to override CML, which is relatively rare,” Sawyers and cancer cells removed from patients, each mutation (3). However, through says of prostate cancer, which kills more showing that cancer cells could be suc- a fortunate turn of fate, Sawyers stumbled than 25,000 men each year in the United cessfully singled out for destruction. The upon a 2002 report in Science from Uni- States alone. Because androgens, or male discovery marked the dawn of a new versity of California, Berkeley structural sex hormones, fuel the growth of cells in era in cancer treatment: molecularly biologist John Kuriyan that described in the prostate gland, missteps in signaling targeted cancer therapy. illuminating detail the crystal structure of could lead to runaway cell division. The the ABL enzyme attached to Gleevec (4). standard approach to keep the cancer Hitting Cancer Where It Hurts Whereas some mutations physically hin- in check involves treatment with anti- The era began in 1995 when Druker and dered Gleevec’s access to the enzyme, the androgen drugs. As with leukemia, some Lydon enlisted the help of Sawyers to plan structure revealed, others changed the patients’ prostate cells develop resistance a multicenter dose and safety clinical trial enzyme’s overall shape. The shape- to the drugs. of Gleevec in patients with CML who changing mutations kept the enzyme in a Using an approach that has now be- failed to respond to IFN therapy, then so-called “on” state that disfavored the come his stock-in-trade in cancer research, the standard treatment for the disease. binding of Gleevec but allowed the en- Sawyers sought to determine what drove For these patients, bone marrow trans- zyme to spur cancer in white blood cells. drug resistance in prostate cells. Drug- plantation, risky and often ineffective, To keep the rebellious cells in check, resistant prostate cells, it turned out, make was the only other recourse. “Brian and I then, Sawyers would need to design drugs unusually high levels of androgen recep- had worked together on cancer signaling, that target the enzyme’s “on” state. tors, which powered their overactive sig- so when he approached me with Gleevec, Thus conceived, the idea yielded dasa- naling, rendering the drugs ineffective and I agreed, and we went to Basel to map tinib, the second-generation blockbuster the cells cancerous (6, 7). To quell the out the trial’s details with Nick Lydon,” drug marketed as Sprycel, thanks to a groundswell of aberrant signals, Sawyers Sawyers says. The trio launched the trial partnership with Bristol–Myers Squibb needed a drug that would gum up the in 1998 with unusually accelerated ap- biochemist Francis Lee (5).

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