Mendelsohn Honored for Taking New Therapy from Concept to Clinic
American Association for Cancer Research award recognizes work in receptors, monoclonal antibodiesM. D. Anderson News Release 04/16/08
For his research illuminating the role of growth factors in cancer cell proliferation, developing a completely new field of therapy to block that process, and then advancing the first drug of its kind to the clinic, University of Texas M. D. Anderson Cancer Center President John Mendelsohn, M.D., has earned a top award from his peers in the American Association for Cancer Research.
Mendelsohn is the 2008 recipient of the Dorothy P. Landon-AACR prize for Translational Cancer Research - research that moves basic science findings into preclinical investigation and then onto clinical trials. The prize is among the largest awards in the world offered to cancer researchers from a professional society of their peers. Honorees receive an unrestricted cash award of $100,000 and present a scientific lecture at the AACR Annual Meeting, with Mendelsohn's presentation set for Monday, April 14.
"The translation of John Mendelsohn's research from the laboratory into clinical practice created a new living with cancer," said AACR Executive Director Margaret Foti, Ph.D., M.D., said. "His dedication and leadership deserve the highest recognition and we are proud to honor John for his revolutionary work."
Mendelsohn praised the AACR and the Kirk A. and Dorothy P. Landon Foundation for highlighting the importance of translational research. "It's most gratifying to receive the Dorothy P. Landon-AACR award. Translational research is a challenging and multi-faceted obstacle course that requires great collaborators, persistence and lots of patience. Awards like this one encourage researchers to take that journey."
The most visible result of Mendelsohn's research is the targeted therapy cetuximab, known commercially as Erbitux®, used today to treat colorectal cancer and head and neck cancers. The first drug of its kind, cetuximab is a monoclonal antibody that interferes with the connection between a growth factor and its surface cell receptor. Today, there are more than 130 clinical trials using cetuximab, known commercially as Erbitux®, to treat 15 types of cancer and two other diseases.
The research and development effort opened an entirely new and unexpected line of attack against cancer.
"Dr. John Mendelsohn had a hunch that paid off. When he identified an antibody against the EGF receptor in the early 1980s, he immediately forged ahead on the path to evaluate and develop this antibody as a treatment for tumors that expressed high levels of the receptor and relied on it for growth," said Stanton L. Gerson, M.D., director of the Case Comprehensive Cancer Center and chair of the Dorothy P. Landon-AACR Prize for Translational Cancer Research selection committee.
"While the path was arduous, as it often is for pioneers in cancer therapy, Dr. Mendelsohn's hypothesis turned out to be spectacular, resulting in a new and effective treatment for many patients with non-small cell lung cancer and head and neck cancer. His work, perhaps the most important new development in cancer therapeutics in the past 20 years, has helped define the field of targeted and personalized therapy for cancer. Rarely does a single discovery have such impact in the field of cancer," Gerson added.
Mendelsohn and colleague Gordon Sato, Ph.D., first floated their hypothesis in 1980 at The University of California-San Diego.
Through their research to understand how growth factors regulate cancer growth by activating receptors on the surface of cells, Mendelsohn and colleagues were the first to propose that blocking the epidermal growth factor receptor (EGFR) could prevent cancer cell growth and reproduction by inhibiting the tyrosine kinase that is part of the receptor. They subsequently proved their hypothesis by developing an anti-EGF monoclonal antibody that could beat the growth factor to its docking station on the receptor, plugging up the receptor. This prevents receptor tyrosine kinase activation and inhibits cancer cell growth.
The team demonstrated this effect in a cell culture in 1983, reported in the Proceedings of the National Academy of Sciences, and in a mouse model with a1984 article in Cancer Research, a journal of the AACR.
C225, or cetuximab, the anti-EGFR monoclonal antibody developed by Mendelsohn, advanced to clinical trials with the first phase I results reported in the Journal of the National Cancer Institute in 1991 for non-small cell lung cancer. This was the first clinical trial of an inhibitor of a growth factor receptor and an inhibitor of a tyrosine kinase. Cetuximab was approved for treatment of advanced colorectal cancer in 2004.
Publications focusing on cetuximab totaled 275 in 2007, up from single digits in the mid-1990s.
One of the trials of translational research is connecting with a biotech or pharmaceutical company to take the drug through final clinical trials and FDA review. From 1990-93, Mendelsohn calls the "impasse" period, no progress was made toward approval. "The solution: find another company," Mendelsohn said, starting with IMClone in 1993 and adding Merck of Germany in 1998 and finally Bristol-Myers Squibb in 2001. Today, tyrosine kinase inhibitors against many different targets are the most common form of new anti-cancer therapy.
While cetuximab is considered a classic early example of targeted cancer therapy, Mendelsohn reminds audiences that the brilliant German physician Paul Ehrlich first developed a theory of targeted therapy against bacterial infection in the late 1890s. After testing his ideas in animal models, he brought forth a variety of drugs that attached to microbes and delivered a toxic agent to kill them. He won the Nobel Prize in 1908 and developed a targeted drug cure for syphilis the following year.
"In 1910, human clinical trials showed efficacy and little toxicity. Salvarsan became standard of care and an early version of a blockbuster drug," Mendelsohn noted in his lecture Monday.
Since becoming president of M. D. Anderson in 1996, Mendelsohn has recruited a visionary management team and overseen a time of tremendous growth and innovation. M. D. Anderson has more than doubled in size and implemented new priorities for integrated programs in patient care, research, education and cancer prevention.
A member of the Institute of Medicine of the National Academy of Sciences, Mendelsohn served as the founding editor of Clinical Cancer Research, a bimonthly translational research journal published by the AACR, and has been a member of the editorial boards of numerous other scientific journals. He has authored more than 300 scientific papers and articles for journals and books, and serves as senior editor of the textbook, "The Molecular Basis of Cancer." Other national and international honors awarded to Mendelsohn, include: the Dan David Prize in Cancer Therapy; the Fulbright Lifetime Achievement Medal; the Bristol-Myers Squibb Freedom to Disc over Award for Distinguished Achievement in Cancer Research; the David A. Karnofsky Memorial Award from the American Society of Clinical Oncology; the AACR-Joseph H. Burchenal Clinical Research Award; and the Gold Medal of Paris. Mendelsohn earned his bachelor's degree in biochemical sciences magna cum laude from Harvard College and received his M.D. cum laude from Harvard Medical School.
The Landon-AACR Prizes in Cancer Research were first presented in 2002 to promote and reward seminal contributions to our understanding of cancer through basic and translational cancer research. These distinguished scientific prizes are designed to bring heightened public attention to landmark achievements in the continuing effort to prevent and cure cancer through quality research. 04/16/08