The BBVA Foundation Frontiers of Knowledge Award in the Biomedicine category is shared in this seventh edition by Tony Hunter, professor and Director of the Salk Institute Cancer Center in La Jolla, California; Joseph Schlessinger, Chairman of the Department of Pharmacology at Yale University School of Medicine, New Haven, and Charles Sawyers, Human Oncology and Pathogenesis Program Chair at the Memorial Sloan Kettering Cancer Center in New York, for “carving out the path that led to the development of a new class of successful cancer drugs.”
27 January, 2015
For José Baselga, Physician-in-Chief at the Memorial Sloan-Kettering Cancer Center in New York and nominator of Charles Sawyers, the three men’s contribution signifies “the birth of personalized anti-cancer medicine.” In the words of the jury, meantime, the award recognizes “the contributions of three eminent scientists who have taken the field all the way from initial basic discoveries to clinical applications that save lives.”
The new treatments, all of them approved in the last ten years, differ from traditional chemotherapy in that they specifically target the mechanisms causing each type of cancer, making them less toxic for the patient. They are, as such, the first dividend of a profound understanding of the biology of cancer rather than scatter-gun molecular test activity. Imatinib, approved in 2001 and the first of this new class of pharmaceuticals, transformed chronic myeloid leukemia from a fatal cancer into one that is nearly always treatable. Now dozens of such “targeted” drugs are in use for lung and breast tumors, melanoma and lymphomas.
The jury remarked that the three laureates have participated independently in a chain of advances running from “the basic discoveries of tyrosine kinase proteins to clinical applications that save lives.”
Tony Hunter, of the Salk Institute, launched the field in 1979 with his discovery of tyrosine kinases, a family of proteins instrumental in regulating vital cell processes like metabolism and proliferation. Some time later, Joseph Schlessinger identified how these tyrosine kinases were activated. And, finally, Charles Sawyers 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,” the citation continues.
Since many human cancers are driven by mutations in tyrosine kinase activity, these proteins and the molecules they interact with have come center stage as therapeutic targets. As the citation explains it: “Today, it is estimated that about a third of pharmaceutical research and development effort goes into targeting tyrosine kinase receptors and their signaling pathways for cancer therapies.”
A product of basic research
The breakthrough that set the story in motion was a product of basic research: the 1979 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.
The next step was the establishment of a link with tumoral processes. This part fell to Schlessinger (Topusko, now Croatia, 1945), who explained by phone after hearing of the award: “Very quickly we found that tyrosine kinase receptors became mutated in cancer. So suddenly it was a big story. There was a mechanism for the information to flow from outside the cell to the interior of the cell and that mechanism was hijacked by cancer.”
'Much more selective and not so toxic'.
From then to midway through the 1990s, “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 continues. “What I mean is that when we started this we did not know it was going to be so important for cancer, and now there are maybe thirty cancer drugs based on this work.” Indeed Schlessinger himself has been behind the development of several.
They are, he adds “much more selective and not so toxic. Most of them cannot be considered a cure, but 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 resistances.”
It is precisely this problem of resistance that is at the heart of Sawyer’s contribution. He recalled yesterday how his group took part in the first human trial of imatinib, a drug that 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.”
'The kind of mutation determines the choice of drug'.
For Sawyers, imatinib was the drug that proved it was possible to fight cancer by acting on a mechanism found through basic research. “In ten years,” he insists, “it has completely changed the approach of the entire pharma industry, at least in cancer.”
And it has also transformed treatment. The concept now is to match the right drug to the right patient after running the relevant genetic tests: “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 points out. “It’s a success story that could never have happened without basic research revealing the deep-seated mechanisms of cancer.”
The next step, he believes, is giving drugs in combination to prevent resistances. “It’s happening already, we are still at the start but now have an approved therapy for melanoma.”
The jury in this category was chaired by Angelika Schnieke, Chair of Livestock Biotechnology in the Department of Animal Sciences of Technische Universität München (TUM) (Germany), with Óscar Marín, Professor of Neurosciences and Director of the MRC Centre for Developmental Neurobiology at King’s College London (United Kingdom), acting as secretary. Remaining members were Dario Alessi, Director of the Protein Phosphorylation Unit, a Medical Research Council unit in the College of Life Sciences of Dundee University (United Kingdom), Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the MRC National Institute for Medical Research (United Kingdom), Ursula Ravens, Senior Professor in the Department of Pharmacology and Toxicology in the Carl Gustav Carus Medical School of Technische Universität Dresden (TU Dresden) (Germany), and Bruce Whitelaw, Deputy Director and Head of the Developmental Biology Division at The Roslin Institute, a basic and translational research center belonging to the University of Edinburgh (United Kingdom).
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