Mendelsohn's Antibody Research Reverberates Today

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.

Exploring Growth Factor Signaling

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.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.

Antibody 225 bound to EGF receptors (EGFRs) on the outside of tumor cells that were grown in cultures. It thereby inhibited the activation of what was then 1 of only 3 known tyrosine kinases inside the tumor cells. This secondary effect shut down a number of key biochemical functions inside the tumor cells and inhibited their proliferation. This raised the hope that the molecule might be able to fight tumors in living organisms.

Mendelsohn and his colleagues tested the theory by pitting antibody 225 (and 2 others they had created) against human tumor cells growing in mice. They noted in a Cancer Research paper in 1984 that the responding tumors had 100 times more EGFRs than the nonresponders before concluding with what turned out to be a significant understatement: “Monoclonal antibodies against growth factor receptors could provide useful immunotherapeutic agents.”

It took another 7 years before Mendelsohn and his colleagues were ready to publish the results of the first trial of antibody 225 in humans. The novelty of the treatment necessitated the reinvention of many development milestones. Indeed, researchers struggled simply to make 225 in sufficient quantities for testing.

“Antibodies today are produced by the kilogram in factories, but we did not have the technology to do that,” Mendelsohn said. “Hybritech, the biotech company that licensed the antibody, produced it in the abdominal cavities of mice, and each mouse could only produce about 1 mg. They needed a huge mouse farm to make enough for our research, and we were still always running short.”

Finally, in 1991, Mendelsohn coauthored the next seminal paper, this time on the first clinical trial of a monoclonal antibody (now called mAb 225) designed to block a receptor and a tyrosine kinase and to alter biological function rather than stimulate an immune response. A purpose of the phase I trial was to demonstrate safety, and it succeeded. No toxicity was observed in any of the patients.

Subsequent trials mostly used the antibody, which came to be known as cetuximab, in combination with chemotherapy, largely because of Mendelsohn’s preclinical work suggesting that an EGFR blockade would slow tumor growth on its own and enhance the efficacy of chemotherapy. This prediction proved entirely correct, but the FDA delayed the approval of cetuximab by demanding a comparative trial that tested it as both monotherapy and combination therapy. The results of the trial showed benefit and secured the drug’s approval, in 2004, for use against advanced colorectal cancer.

Expanding MD Anderson’s Influence

“John’s work on what became cetuximab illustrates just how tenacious he is,” said Waun Ki Hong, MD, who formerly chaired MD Anderson’s Division of Cancer Medicine and has known Mendelsohn for more than a quarter-century. “It’s not like the scientific community was excited about the potential of signaling pathways in the late 70s and early 80s. He spent more than a decade trying to sell very skeptical observers on his vision. But he never gave up. He kept at it and kept at it until he validated his ideas and opened up an entirely new way to attack cancer.”While cetuximab and another monoclonal antibody, trastuzumab (Herceptin), were moving through the clinical trials that signaled the beginning of the targeted therapy era, Mendelsohn took on a new job as president of MD Anderson, a post he held from 1996 to 2011.

Mendelsohn had spent most of his professional career balancing administrative duties with scientific research and modest clinical activities. He ran a research lab while he directed UCSD’s cancer center from 1976 to 1985 and while he chaired the Department of Medicine at MSK from 1985 to 1996. When he took the helm of MD Anderson, though, he realized that the job would demand all of his attention.

MD Anderson ranked among the nation’s top cancer centers long before Mendelsohn arrived. Its first 2 presidents recruited top talent like Emil J. Freireich, MD (another Giants of Cancer Care^® award winner), who, in turn, attracted talented younger doctors and established a world-class center for research and clinical care.

Mendelsohn used that very strong foundation to build—a lot. The hospital added more than 10 million square feet during his tenure and more than doubled its patient care activities. In part, the expansion was a response to a new state law. Until then, patients needed a physician’s referral to seek care at MD Anderson. After 1995, they were free to seek care on their own. Access to a world-class cancer center naturally increased patient numbers and enabled expansion.

As this was happening, Mendelsohn enacted a plan to boost MD Anderson from a top cancer center to a serious contender to be the top cancer center. “I had a vision that MD Anderson should make itself the leading place in the country for translational research, for taking the basic discoveries made all around the world and pioneering their use in clinical care,” he said. “For example, a lot of research back then showed the importance of interdisciplinary care but surgeons, medical oncologists, and radiation oncologists worked in totally separate departments. We had decided to organize around cancer types, rather than treatment types, so the different physicians who treated a single patient would form a single team. That’s common now, but Anderson was the first place to pioneer it, and it helped produce significantly better clinical, research, and treatment outcomes.”

Mendelsohn launched the largest fundraising drive in MD Anderson history. He set an initial goal of $1 billion, which some thought impossible, and then reached that goal 2 years ahead of schedule. He next raised the goal to $1.2 billion and reached that. The money built laboratories, endowed chairs, and expanded clinical facilities. US News & World Report ranked MD Anderson the nation’s top cancer hospital for 6 of Mendelsohn’s last 8 years as president.

“What John accomplished, as an administrator, when he ran MD Anderson was, as far as I can tell, unprecedented in the history of cancer centers,” said Leon Leach, PhD, who served as MD Anderson’s executive vice president for business and finance during Mendelsohn’s tenure. “He quadrupled the size of the organization in terms of revenue and he improved quality at exactly the same time. When is the last time you saw any type of organization get significantly better in the middle of a massive growth spurt?”

Mendelsohn’s work left him with relatively little time for a normal home life, but he was lucky enough to marry a fellow scientist who supported his passion for discovery. Indeed, the work Anne Mendelsohn did for Polaroid (which earned her 2 patents) helped finance John Mendelsohn’s years at medical school and provide some creature comforts during what would have been very lean years of postdoctoral study.

Mendelsohn tried to pay her back by working only in world-class cities where she wanted to live and by leaving his job behind during their vacations. He was also at home for dinner with Anne and their 3 sons every night he was in town. “I worked hard, but I played hard, too,” he said. “I made sure to pack the time I had with them with as many good experiences as I could.”