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.
1955.04.30出生
Place of Birth:St. Louis, Missouri, USA
Nationality:USA
Field of Specialization:Cancer Biology, Medicine and Translational Research
Education
1981 M.D., University of California School of Medicine, San Diego, USA
1977 B.A., Chemistry, University of California, San Diego, USA
Professional Experience
- 2007-Present
- Director, OHSU Cancer Institute (renamed the Knight Cancer Institute in 2008), Oregon Health & Science University (OHSU), USA
- 2002-Present
- Investigator, Howard Hughes Medical Institute, USA
- 2000-Present
- Professor of Medicine, Division of Hematology & Medical Oncology, OHSU, USA
- 1996–2002
- Director / Associate Director, OHSU MD/PhD Program, USA
- 1996-present
- Joint Appointment, Department of Biochemistry and Molecular Biology, OHSU, USA
- 1993-present
- Co-Director, Center for Hematologic Malignancies, OHSU Cancer Institute, USA
- 1993-present
- Program Leader, Hematologic Malignancies, OHSU Cancer Institute, USA
- 1993-present
- Joint Appointment, Department of Cell and Developmental Biology, OHSU, USA
- 1993-2000
- Associate Professor, Department of Medicine, OHSU, USA
- 1993-present
- Staff Physician, University Hospital and Clinics, OHSU, USA
- 1987-1993
- Instructor in Medicine, Harvard Medical School, Boston, MA, USA
- 1987-1993
- Medical Director, Nashoba Community Hospital, Oncology Clinic, Ayer, MA, USA
- 1987-1993
- Associate Physician, Brigham and Women's Hospital, Boston, MA, USA
- 1987-1993
- Clinical Associate, Dana-Farber Cancer Institute, Boston, MA, USA
- 1984-1987
- Fellowship in Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- 1981-1984
- Internship and Residency in Internal Medicine , Barnes Hospital, Washington University School of Medicine, St. Louis, MO, USA
Awards & Recognition
- 2017
- ASCO Science of Oncology Award and Lecture
- 2017
- Outstanding Alumnus, University of California, San Diego
- 2016
- Doctor of Science, Honorary Degree, Albany Medical College
- 2015
- Award for Excellence in Molecular Diagnostics, Association for Molecular Pathology
- 2015
- Duane Roth Award, UCSD Moores Cancer Center
- 2014
- Hamdan Award for Medical Research Excellence, Sheikh Hamdan Bin Rashid Al Maktoum Awards for Medical Sciences
- 2013
- Doctorate, Honorary, Erasmus University, Rotterdam
- 2013
- Taubman Prize for Excellence in Translational Medical Science
- 2013
- AACI Distinguished Scientist Award, Association of American Cancer Institutes
- 2013
- Giants of Cancer Care, OncLive
- 2013
- The Albany Medical Center Prize in Medicine and Biomedical Research
- 2013
- Doctor of Humane Letters, Honorary Degree, University of Portland
- 2013
- UCSF Medal, University of California San Francisco
- 2012
- Elected member, American Academy of Arts and Sciences
- 2012
- Dickson Prize in Medicine, University of Pittsburgh School of Medicine
- 2012
- The Japan Prize in Healthcare and Medical Technology, The Japan Prize Foundation
- 2011
- Ernest Beutler Lecture and Prize, American Society of Hematology
- 2011
- Stanley J. Korsmeyer Award, American Society for Clinical Investigation
- 2010
- Vollum Award for Distinguished Accomplishment in Science and Technology, Reed College: Division of Mathematics and Natural Sciences, Portland
- 2010
- Doctor of Science, Honorary Degree, Washington University
- 2010
- The Robert J. and Claire Pasarow Foundation Cancer Award
- 2010
- Inaugural Member, GIST Hall of Fame, The Life Raft Group
- 2010
- 35th Jeffrey A. Gottlieb Memorial Award, University of Texas M.D. Anderson Cancer Center
- 2009
- The Alexander Bodini Foundation Prize for Scientific Excellence in Medicine, American-Italian Cancer Foundation
- 2009
- Meyenburg Award for Cancer Research, Meyenburg Foundation, Heidelberg, Germany
- 2009
- Lasker-DeBakey Clinical Medical Research Award, Albert and Mary Lasker Foundation
- 2009
- The Rowley Prize, International CML Foundation
- 2009
- Hope Funds Award of Excellence: Clinical Development, The Hope Funds for Cancer Research
- 2009
- European Inventor of the Year 2009, European Patent Office and European Enterprise: DG Enterprise and Industry
- 2008
- The Simon M. Shubitz Cancer Prize and Lectureship, The University of Chicago Cancer Research Center and The University of Chicago Cancer Research Foundation
- 2008
- 13th Annual Alfred G. Knudson Award Lecture in Cancer Genetics, National Cancer Institute
- 2007
- Keio Medical Science Prize, Keio University Medical Science Fund, Tokyo, Japan
- 2007
- 2006-2007 Teaching Excellence Award, OHSU School of Medicine
- 2007
- Golden Plate Award, Academy of Achievement
- 2007
- Elected Member, National Academy of Sciences, USA
- 2006
- Elected Member, American Association of Physicians, USA
- 2006
- Technology Innovation Award, OHSU
- 2006
- STAR Medical Research Award, Angel Foundation
- 2005
- Technology Innovation Award, OHSU
- 2005
- Robert-Koch Prize, Robert Koch Foundation, Cologne, Germany
- 2005
- Biotech Hall of Fame Award for Scientific Achievement, The Biotech Meeting
- 2005
- David Nathans Memorial Award, Van Andel Institute
- 2004
- Naomi M. Kanof Clinical Investigator Award, The Society for Investigative Dermatology
- 2004
- Doctor of Science, Honorary Degree, State University of New York
- 2004
- Dr. Alvin J. Thompson Award, Northwest Association for Biomedical Research
- 2004
- Outstanding Program Award, Center for Diversity and Multicultural Affairs, OHSU
- 2004
- Humanitarian Award, The Life Raft Group
- 2003
- Elected Member, National Academy of Medicine (Institute of Medicine), USA
- 2003
- Braunschweig Preis, City of Braunschweig
- 2003
- David A. Karnofsky Award, American Society of Clinical Oncology
- 2003
- Days of Molecular Medicine Translational Medicine Award, UC San Diego-Nature Medicine
- 2002
- International Citizen Award, Oregon Consular Corps
- 2002
- Novartis-Drew University Award in Biomedical Research
- 2002
- City of Medicine Award, Durham Health Partners, Inc.
- 2002
- Charles F. Kettering Prize, General Motors Cancer Research Foundation
- 2002
- Medal of Honor, American Cancer Society
- 2002
- Pioneer of Survivorship Carpe Diem Award, Lance Armstrong Foundation
- 2002
- Alexandra J. Kefalides Prize for Leukemia Research, University of Pennsylvania Cancer Center
- 2002
- Donald Ware Waddell Award Lecture, Arizona Cancer Center
- 2001
- JELD-WEN Chair of Leukemia Research, JELD-WEN, Klamath Falls, Oregon
- 2001
- Dameshek Prize, The American Society of Hematology
- 2001
- Warren Alpert Foundation Prize, Harvard Medical School
- 2001
- Emil J. Freireich Award, The University of Texas MD Anderson Cancer Center
- 2001
- AACR-Richard and Hinda Rosenthal Foundation Award
- 2001
- Charles Rodolphe Brupbacher Prize for Cancer Research
- 2000
- John J. Kenny Award, The Leukemia and Lymphoma Society
- 2000
- Outstanding Alumnus, University of California, San Diego
- 2000
- Translational Research Award, Burroughs Wellcome Fund
- 2000
- Lifetime Achievement Award, The Leukemia and Lymphoma Society, Washington Chapter
- 1999
- Discovery Award, Oregon Health Sciences Foundation
- 1998
- Teaching Award, OHSU 2nd Year Medical School Class
- 1997
- Elected member, American Society for Clinical Investigation
- 1977
- B.A. Summa Cum Laude, University of California, San Diego
- 1977
- Phi Beta Kappa
- 1976
- President's Undergraduate Research Award - University of California, San Diego
Publications (Selected)
- 2014
- Ma L, Shan Y, Bai R, Xue L, Eide CA, Ou J, Zhu LJ, Hutchinson L, Cerny J, Khoury HJ, Sheng Z, Druker BJ, Li S, Green MR. (2014) A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 6(252): 252ra121
- 2009
- Druker BJ. (2009) Perspectives on the development of imatinib and the future of cancer research. Nat Med. 15(10):1149-52
- 2001
- Druker BJl, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 344(14):1031-7.