John Mendelsohn, MD
John Mendelsohn, MD, developed and launched what is now known as the Moores Cancer Center at the University of California, San Diego (UCSD), where he served as its founding director. He next chaired the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK). Then he served as president of The University of Texas MD Anderson Cancer Center for a 15-year period that saw that institution’s size triple and its budget quadruple.
But the man who may have been the most successful administrative oncologist of his era probably won’t be remembered as an administrator. Mendelsohn was also a pioneering researcher who helped demonstrate the vital role that signaling pathways play in tumor growth, aided in developing the first antibody to block a signaling pathway, and established a template for testing those agents and getting them approved. “In 1991, when we reported the results of the clinical trials, we ran on what’s now called cetuximab (Erbitux). It was the first-ever trial of an agent that blocked a growth factor receptor and the first-ever trial of an agent that inhibited a tyrosine kinase. Now, the majority of all cancer trials are testing agents that block growth factor receptors and inhibit a tyrosine kinase,” said Mendelsohn, who is director of the Khalifa Institute for Personalized Cancer Therapy and a professor in the Department of Genomic Medicine at MD Anderson. “In some ways, I worked on a single 20-year research project, but each step led so naturally into the next that I had to keep going. I’m just happy I was able to see it through and that my work has had a real impact on so many patients.”
Mendelsohn grew up in Cincinnati and did well enough in the public school system to earn a spot at Harvard University, where he was a premed major and a Fulbright Scholar. Starting in the summer just after his sophomore year, he worked as an assistant to a new professor, James Watson, who went on to share the Nobel Prize in Physiology or Medicine for discovering the structure of DNA. Mendelsohn’s work with Watson cemented his desire to perform medical research. It also garnered him his first publication: a paper that described how the presence of food signals bacteria to move from a resting phase to a proliferation phase and synthesize new RNA, and how the exhaustion of that food supply signals the bacteria to rest once more and reduce their RNA content. It was a very elemental version of the growth signaling process that was to dominate his research for decades to come.
After Mendelsohn’s undergraduate studies, he spent his Fulbright year at the University of Glasgow, researching DNA and aspects of cell growth regulation. He then returned to Harvard for medical school, completed his residency at Brigham and Women’s Hospital, and undertook further study at the National Cancer Institute and Washington University. Having excelled at each of these short-term stops, he was ready, by 1970, to settle down at UCSD, which wanted Mendelsohn to join its new medical school and help design the cancer center it hoped to open. Mendelsohn taught at the school; designed the cancer center and, as previously mentioned, was its founding director; and cared for patients. During this time, however, his main focus was still his research.
Mendelsohn ran a research lab at UCSD that focused, during those years, on lymphocytes that proliferated when they were exposed to a lectin called phytohemagglutinin, which bound to receptors on the cell surface. Mendelsohn systematically studied the interaction between the lectin and the lymphocytes, and he explored the chemical pathway that initiated the proliferation.
Exploring Growth Factor Signaling
He then teamed up with Gordon H. Sato, PhD, a fellow researcher who also had spent a decade figuring out how to make cells grow in cultures without the addition of serum. Sato’s work revealed that many cells would not grow without a blood-borne compound that was dubbed epidermal growth factor (EGF), which bound to receptors on the cell surface.
Mendelsohn and Sato learned that EGF, although different from phytohemagglutinin, signaled most cells to proliferate much as phytohemagglutinin signaled lymphocyte cells. They then decided to attempt something that would forever change the way cancer is treated: they set out to create and deploy a molecule that would prevent EGF from binding to receptors on tumor cells and thereby prevent it from stimulating proliferation.
“The plan was to make an antibody that would bind to the tumor in the same place as the epidermal growth factor would otherwise bind. Technology had just gotten to the point that it was possible to develop such an antibody. It wasn’t very quick or easy, though. In all, we spent 3 years with a team of postdoctoral students and scientists producing the molecule that eventually went into clinical trials, which we called antibody 225,” Mendelsohn said.