A Spanish foundation has awarded a major scientific prize to Yale researcher Joseph Schlessinger, PhD, and two colleagues in recognition of their work leading to the first personalized treatments for cancer. The 2015 Frontiers of Knowledge Award in Biomedicine from the Madrid-based BBVA Foundation includes a €400,000 cash prize.
Schlessinger, the William H. Prusoff Professor of Pharmacology, shares the prize with Tony Hunter, PhD, of the Salk Institute and Charles L. Sawyers, MD, of Memorial Sloan Kettering Cancer Center, for “carving out the path that led to the development of a new class of successful cancer drugs.”
The drugs, all of them approved since 2001, target mechanisms specific to various cancer subtypes and carry fewer side effects. The first of this new class of pharmaceuticals, imatinib (marketed as Gleevec), transformed chronic myeloid leukemia from a fatal cancer into one that is nearly always treatable. Dozens of similar targeted drugs are in use for lung and breast tumors, melanoma, and lymphomas.
Discoveries in cell signaling
Hunter launched the field in 1979 with his discovery of tyrosine kinases, a family of proteins instrumental in regulating vital cell processes including metabolism and proliferation. 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. Sawyers applied a tyrosine kinase inhibitor in the clinic for cancer therapy and found a way to interfere with their activity in the presence of mutation, “leading to the clinical translation of these basic concepts into the treatment of cancer,” according to the awards panel, which included scientists from King’s College London, Dundee University, the MRC National Institute for Medical Research, the University of Edinburgh, Technische Universität (TU) München, and TU Dresden.
The initial breakthrough in 1979 was 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, inducing a cascade of signals with a vital role in regulating cell proliferation and multiple other processes. Hunter’s work, together with that of many others, has shown that aberrant tyrosine phosphorylation enables several types of human cancer and other diseases. His discovery of tyrosine phosphorylation launched a new area of research, with over 70,000 papers published.
Schlessinger discovered a mechanism, known as receptor dimerization, that explains how receptor tyrosine kinases are activated when a molecule binds at the cell surface. He also identified key molecules and mechanisms that relay signals from outside the cell, through the cell membrane, to the interior of the cell. This principle has proven to be fundamental to activation of the majority of surface receptors and for information flow from the cell surface into intracellular compartments.
Hijacked by cancer
“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 said. “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, chair of the Department of Pharmacology and 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 Robert J. Alpern, MD, dean of Yale School of Medicine. “He then translated these discoveries into the development of FDA-approved drugs through companies that he founded, Sugen, Plexxikon, and Kolltan.”
Schlessinger noted that while most in the new class of targeted therapies cannot be considered a cure, “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.”
Overcoming resistance is at the heart of Sawyer’s contribution. He recalled how his group took part in the first human trial of imatinib, which is “very selective in its action because it only attacks the mutating protein in chronic myeloid leukemia, so has no side effects. When patients began to develop resistance our lab figured out why: there were additional mutations in the gene encoding the protein that imatinib targets. So, based on that, we developed another agent, desatinib, that inhibits the same protein but in a different way.”
Sawyers said that imatinib proved it was possible to fight cancer by acting on a mechanism found through basic research. “In 10 years,” he said, “it has completely changed the approach of the entire pharma industry, at least in cancer.”
It has also transformed treatment, by matching therapy to the genomic profile of the tumor. “The kind of mutation determines the choice of drug. Now we know hundreds of mutations, and have progressed in no time at all from having imatinib alone to having dozens of drugs that act upon them,” Sawyers said. “It’s a success story that could never have happened without basic research revealing the deep-seated mechanisms of cancer.”
Schlessinger sits on the editorial boards of leading scientific journals such as EMBO Journal, Cell, Molecular Cell, and Molecular Biology of the Cell. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine, and the European Molecular Biology Organization. In 2001, ISI Highly Cited listed him among the 30 most cited scientists of the 1990s, with over 76,000 citations.
This article is based on a news release from the BBVA Foundation. For the original release, the full citation, and video from the news conference announcing the prize, visit http://ht.ly/I1EHw.