Tyrosine kinase inhibitors (TKIs) are the prototypes of targeted therapies, which already have significant impacts on the treatment of cancer patients. Dr. Tony Hunter, Professor of Biology at the Salk Institute, gave birth to this field by discovering tyrosine phosphorylation and that the oncogene src is a tyrosine kinase. At that time, it was already known that kinases are enzymes that can attach phosphates on the amino acids serine and threonine of a protein, but the discovery that tyrosine could also be phosphorylated revealed a brand new level of cellular regulation critically involved in development and disease. In the human genome, the tyrosine kinase family represents a minor class of protein kinases, but they are a major family of oncogenes (cancer-inducing genes). This is because many of them are receptors on the cell surface and are critically involved in transmitting signals to instruct cells to grow in response to environmental cues such as growth factors. Upon mutations, they become constitutively active and no longer require environmental cues to trigger a response. Cells would then grow incessantly, eventually becoming malignant.
As demonstrated later, shutting off the oncogenic tyrosine kinase signals by small molecules or antibodies indeed stops cancer cell growth and is an effective way to treat cancers. Mutated or activated tyrosine kinases have become superb diagnosis and prognosis markers for cancer. In addition to growth, tyrosine kinases are now found to function in cell migration, survival and other malignant phenotypes. Dr. Hunter’s discovery in 1979 at the Salk Institute paved the road for the next twenty years’ active research on tyrosine kinase oncogenes, leading to the development of TKIs (tyrosine kinase inhibitors). The field is still going strong almost forty years after his discovery. He also showed that cancer cells are highly tyrosyl-phosphorylated, and with his colleague, Bart Sefton, developed anti-phosphotyrosine antibodies, a very powerful tool for studying cancer signals and identifying TKIs. Thus, it is no exaggeration to say Dr. Tony Hunter opened up the “tyrosine kinase field” and brought forth the golden era of signal transduction research. The current success of targeted therapy owes a great deal to him.
Dr. Brian Druker, Director of Oregon Health Sciences University Knight Cancer Institute, is the physician scientist who led the successful clinical trial of imatinib (Gleevec®) on chronic myelogenous leukemia (CML), which opened up the field of TKI as targeted therapy. Gleevec shuts off oncogenic signals by inhibiting Abl tyrosine kinase (translocated as Bcr-Abl oncogene in CML), as predicted by Tony Hunter’s original hypothesis. Abl is a tyrosine kinase, the gene of which upon translocation to a different chromosomal site (Bcr [breakpoint cluster region]) becomes constitutively active. In addition to Abl, Gleevec also inhibits Kit, PDGF and other tyrosine kinase oncoproteins. It has been useful in the treatment of acute lymphocytic leukemia (ALL) and certain types of gastrointestinal stromal tumors (GISTs) where Kit is overexpressed. Now there are more than 29 TKIs which have been approved for clinical use. Clearly, Dr. Druker’s first successful trials heralded this still burgeoning targeted therapy era. Dr. Druker was also involved in the development of the 4G10 antibody (at Thomas Robert’s lab) which recognizes phosphotyrosine and was used by Novartis colleagues in the screening of Gleevec. Thus, Dr. Druker’s contributions are in both the development and application of Gleevec, which was the first successful example of tyrosine kinase-targeted therapy by small molecule inhibitors.
Dr. John Mendelsohn, President Emeritus of MD Anderson Cancer Center, took another approach while at UC San Diego working with Dr. Gordon Sato. An alternative way of shutting off the activities of tyrosine kinases on the cell surface (receptor tyrosine kinase) is to develop antibodies against the extracellular domain of the receptor. In such a way, the natural ligand (e.g., growth factor) can no longer bind, thus the receptor tyrosine kinase is no longer activated. They conceived the idea that antibodies targeting epidermal growth factor receptor (EGFR) may be an effective strategy for cancer treatment. EGFR is the prototype of receptor tyrosine kinases, located on the cell surface and a main engine to drive cell growth. It is often overexpressed or mutated to become oncogenic in different types of cancer. Dr. Mendelsohn and his team conducted preclinical research and proceeded to develop the anti-EGFR antibody cetuximab (Erbitux®). His effort to promote it into clinics eventually won the approval of the US FDA for the treatment of colon cancer and head/neck cancer. This was the first clinically approved therapy using an antibody to inhibit the tyrosine kinase of a growth factor receptor and a trail-blazer which has spurred many others to follow.
In summary, the discovery of protein tyrosine phosphorylation and tyrosine kinases sowed the seed for research in the ensuing forty years leading to a thorough understanding of the fundamental principles of cell growth and cancer development. The development of tyrosine kinase-targeted therapies has fundamentally changed the practices of cancer clinics. It provides great benefits to patients who suffer from this dreadful disease and gives hope that cancer can eventually be treated. The contributions of this years’ Tang Prize in Biopharmaceutical Science awardees to science and society are immeasurable. Their accomplishments amply illustrate how brilliant basic science can lead to clinical applications that benefit all mankind.
Date of Birth:1936.08.31
Place of Birth:Cincinnati, Ohio, USA
Nationality:USA
Field of Specialization:Oncology, Medicine
Education
1963 M.D., Medicine, Harvard Medical School, Boston, MA, USA
1959 Fulbright Scholar, Molecular Biology, University of Glasgow, Scotland, UK
1958 B.A., Biochemical Science, Harvard University, Cambridge, MA, USA
Professional Experience
- -2018
- L.E. and Virginia Simmons Senior Fellow in Health and Technology Policy, Rice University, James A. Baker III Institute for Public Policy, Houston, TX, USA
- -2018
- Professor, Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 2011-2018
- Director, Institute for Personalized Cancer Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 1998-2018
- Member, Graduate Faculty, Graduate School of Biomedical Sciences, Houston, TX, USA
- 1996-2018
- Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 1996-2011
- President, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 1985-1996
- Professor, Medicine, Cornell University Medical College, New York, NY, USA
- 1985-1996
- Attending Physician, Memorial Hospital, New York, NY, USA
- 1985-1996
- Chairman, Department of Medicine, Memorial, New York, NY, USA
- 1985-1996
- Vice-Chairman, Medicine, Cornell University Medical College, New York, NY, USA
- 1985-1990
- Co-Chairman, Sloan-Kettering Institute for Cancer Research, New York, NY, USA
- 1979-1985
- Professor, University of California, San Diego, CA, USA
- 1976-1986
- Founding Director of Cancer Center, University of California, San Diego, San Diego, CA, USA
- 1976-1985
- Co-Head, Hematology/Oncology, University of California, San Diego, San Diego, CA, USA
- 1974-1979
- Associate Professor, University of California, San Diego, San Diego, CA, USA
- 1970-1974
- Assistant Professor, University of California, San Diego, CA, USA
- 1968-1970
- Fellow, Hematology/Oncology, Washington University, St. Louis, MO, USA
- 1967-1968
- Senior Resident, Medicine, Peter Bent Brigham Hospital, Boston, MA, USA
- 1967-1968
- Assistant, Medicine, Harvard Medical School, Boston, MA, USA
- 1965-1967
- Research Associate, Molecular Biology, National Institutes of Health, Bethesda, MD, USA
- 1964-1965
- Assistant Resident, Medicine, Peter Bent Brigham Hospital, Boston, MA, USA
- 1963-1964
- Clinical Internship, Medicine, Peter Bent Brigham Hospital, Boston, MA, USA
Awards & Recognition
- 2017
- Strategic Management Society Lifetime Achievement Award 2017, Jesse H. Jones Graduate School of Business, Rice University
- 2017
- Rell Sunn Award 2017, Moores Cancer Center at University of California San Diego
- 2016
- Award of Excellence, Hope Funds for Cancer Research
- 2016
- Lifetime Achievement Award, Indo-American Chamber of Commerce of Greater Houston (IACCGH)
- 2015
- History-Making Texas Award, Texas State History Museum Foundation
- 2014
- Recognized as one of ASCO's Oncology Luminaries (50th Anniversary), American Society for Clinical Oncology (ASCO)
- 2013
- Geoffrey Beene Builders of Science Award, Research!America (Benefactor: The Geoffrey Beene Foundation)
- 2013
- Elected Fellow, American Academy of Arts and Sciences
- 2013
- Helmholtz International Fellow Award, German Cancer Research Center in the Helmholtz Association
- 2013
- PTV Star of Excellence Award, PTV Sciences
- 2012
- Sixth Annual American Association for Cancer Research Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research, American Association for Cancer Research
- 2012
- Charles A. LeMaistre, M.D. Outstanding Achievement Award in Cancer
- 2011
- Medal of Honor, American Cancer Society
- 2011
- Heath Memorial Award, The University of Texas M.D. Anderson Cancer Center
- 2010
- Ernest W. Bertner Memorial Award, The University of Texas M.D. Anderson Cancer Center
- 2009
- Lila Gruber Memorial Cancer Research Award, American Academy of Dermatology
- 2009
- Lifetime Achievement Award, 10th International Workshop on Molecular Targeted Therapy of Cancer
- 2008
- Dorothy P. Landon − AACR Prize for Translational Cancer Research, American Association for Cancer Research
- 2007
- The Norman Vincent and Ruth Stafford Peale Humanitarian Award. Jointly awarded with his wife, Guideposts
- 2007
- AICF Prize for Scientific Excellence in Medicine (jointly with Dr. Jose Baselga), American-Italian Cancer Foundation
- 2006
- Future Time Dimension - in the Field of Cancer Therapy, Dan David Prize and Dan David Foundation
- 2006
- Loving Hearts and Caring Hands Award, The University of Texas M. D. Anderson Cancer Center
- 2006
- Honorary Doctorate Degree, Yonsei University, Seoul Korea
- 2006
- Honorary Doctorate Degree, China Medical University, Taichung, Taiwan
- 2005
- Fulbright Lifetime Achievement Medal
- 2005
- Honorary Doctorate Degree, Naples University, Italy
- 2004
- 27th Bristol-Myers Squibb Freedom to Discover Award for Distinguished Achievement in Cancer Research, Bristol-Myers Squibb
- 2002
- Simon M. Shubitz Award, University of Chicago Cancer Center Research Foundation
- 2002
- David A. Karnofsky Memorial Award, American Society of Clinical Oncology
- 1999
- 4th Joseph H. Burchenal American Association for Cancer Research Clinical Research Award, American Association for Cancer Research
- 1999
- Elected Member, Royal Netherlands Academy of Arts and Sciences
- 1997
- Elected Member, National Academy of Medicine (Institute of Medicine), USA
- 1997
- Raymond Bourgine Award for Excellence in Cancer Research
- 1997
- Bristol-Myers Squibb Cancer Research Award
- 1997
- Gold Medal of Paris
- 1997
- Phi Beta Kappa Outstanding Alumnus Award, Phi Beta Kappa Alumni of Greater Houston
- 1997
- Jill Rose Award for Outstanding Breast Cancer Research, Breast Cancer Research Foundation
- 1990
- Merit Award, National Cancer Institute Grant
- 1985
- "Headliner of the Year" in Medicine, Press Association
- 1982
- Professor of Clinical Oncology, American Cancer Society
- 1973
- Research Career Development Award, National Institutes of Health
- 1963
- First Prize, Boylston Society Essay Contest, Harvard Medical School
- 1962
- Alpha Omega Alpha, Harvard Medical School
- 1958
- Phi Beta Kappa, Harvard College
- 1958
- United States Fulbright Scholar in Biochemistry, University of Glasgow, Scotland
Publications (Selected)
- 2000
- Baselga J, Pfister D, Cooper MR, Cohen R, Burtness B, Bos M, D'Andrea G, Seidman A, Norton L, Gunnet K, Anderson V, Waksal H, Mendelsohn J. (2000) Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18: 904-914
- 1991
- Divgl CR, Welt C, Kris M, Real FX, Yeh SDJ, Grana R, Merchant B, Schweighart S, Unger M, Larson SM, Mendelsohn J. (1991) Phase I and Imaging trial of Indium-111 labeled anti-EGF receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. J Natl Cancer Inst 83:97-104
- 1984
- Masul H, Kawamoto T, Sato JD, Wolf B, Sato GH, Mendelsohn J. (1984) Growth inhibition of human tumor cells in athymic mice by anti-EGF receptor monoclonal antibodies. Cancer Res 44:1002-1007
- 1984
- Glll GN, Kawamoto T, Cachet C, Le A, Sato JD, Masul H, McLeod C, Mendelsohn J. (1984) Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259:7755-7760
- 1983
- Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. (1983) Growth stimulation of A431 cells by EGF: Identification of high affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 80:1337-1341