Hormones such as insulin and growth factors mediate their many physiological responses by activating a family of enzymes known as tyrosine kinases. Because of their roles as “drivers” of many cancers, tyrosine kinases have become a favorite target within the field of personalized cancer therapy: as of today, 20 cancer drugs targeting them have now been approved by the FDA. Yale’s Joseph Schlessinger, Ph.D., chair and the William H. Prusoff Professor of Pharmacology, has researched the underpinnings of these enzymes for more than three decades.
The work of Schlessinger and two colleagues has now garnered them the 2015 Frontiers of Knowledge Award in Biomedicine from the Madrid-based Fundación BBVA. Schlessinger shares the award, which carries a €400,000 cash prize, with Tony Hunter, Ph.D., of the Salk Institute, and Charles L. Sawyers, M.D., of Memorial Sloan Kettering Cancer Center. According to the Fundación’s awards panel, they helped blaze the “path that led to the development of a new class of successful cancer drugs.”
For his part, Schlessinger identified how receptor tyrosine kinases are activated, how mutations in receptor tyrosine kinases cause cancer, and how tyrosine kinases can be blocked to treat cancer. He discovered a mechanism, known as receptor dimerization, that explains how receptor tyrosine kinases are activated when a molecule binds at the cell surface. “We found a mechanism for information flow from outside the cell to the interior of the cell, and how this mechanism was hijacked by cancer,” Schlessinger says. “We explored the way these signaling pathways operated, and it became clear that if we developed inhibitors we could have drugs to treat cancer.”
Schlessinger, also director of the Yale Cancer Biology Institute, has had an exceptional record of research “that reflects a creative experimental approach, spanning molecular, genetic, and structural studies to explore fundamental and important questions in biomedical science,” said Dean and Ensign Professor of Medicine Robert J. Alpern, M.D. “He then translated these discoveries into the development of FDA-approved drugs through companies that he founded, Sugen, Plexxikon, and Kolltan.”
Schlessinger notes that while most drugs in the new class of targeted therapies cannot be considered cures, “they do extend life expectancy, which is a real revolution. These new drugs, moreover, are based on an understanding of what causes cancer. And that is why we can talk about personalized medicine. Even so, we are only scratching at the surface. Cancer is a very complicated disease, and the challenge now is how to overcome resistance.”
In 1979 the field experienced a breakthrough with the discovery of the tyrosine kinase that enables the cell to perceive its environment. Like a key, it opens a specific door in the cell membrane and induces a cascade of signals that work to regulate cell proliferation and other processes. The work of the three scientists has shown how aberrant tyrosine phosphorylation enables some cancers and other diseases.
Schlessinger sits on the editorial boards of leading journals such as EMBO Journal, Cell, and Molecular Cell. He is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the European Molecular Biology Organization. In 2001, the Institute for Scientific Information listed him among the top 30 most cited scientists of the 1990s.