2010 - Joseph Schlessinger

Yale University School of Medicine
Department of Pharmacology, New Haven, CT


Motivation:

Dr. Joseph Schlessinger is honored in recognition of his groundbreaking basic discoveries in cancer research. He has worked tirelessly to exploit them for clinical use in cancer patients and has succeeded to a significant degree. Many cancer patients across the world are now benefiting directly from the combination of his superb science and his commitment to translating it for the benefit of patients.
Dr. Schlessinger's pioneering studies have paved the way for the discovery of new families of cancer drugs that inhibit receptor tyrosine kinases (RTKs), including Sutent (SU11248/sunitinib), a drug developed by Dr. Schlessinger’s team at Sugen that was approved by the FDA in 2006 for both the treatment of renal cancers and gastrointestinal stromal tumors (GIST).
Dr. Schlessinger was the first to demonstrate that epidermal growth factor (EGF) binding induces dimerization of the epidermal growth factor receptor (EGFR), and to propose that ligand-induced receptor dimerization is crucial in activation of (and signaling by) the receptor. This work actually predated the findings that EGFR and the insulin receptor are protein tyrosine kinases. His lab also generated the first monoclonal antibodies (mAbs) against EGFR, permitting numerous seminal experiments including the key studies showing that receptor dimerization is both necessary and sufficient for activation of EGFR’s tyrosine kinase activity. The Schlessinger laboratory used these antibodies to purify and clone EGFR, allowing the first biochemical studies with the purified receptor.
Dr. Schlessinger’s laboratory was also the first to show that co-expression of a truncated EGFR interferes with activation of full-length EGFR. This dominant-negative effect, mediated by heterodimerization of mutated and wild-type EGFR, provided the most compelling evidence to date that dimerization is critical for receptor tyrosine kinase (RTK) activation in vivo. His laboratory went on to show that RTKs become autophosphorylated through an intermolecular ‘cross-phosphorylation’ process and – unexpectedly – that the primary target for EGFR is actually EGFR itself. They proceeded to identify all of the tyrosine autophosphorylation sites of EGFR and ErbB2.
A major conceptual breakthrough was achieved when Dr. Schlessinger’s lab showed that phospholipase-Cγ (PLCγ), a key EGFR substrate, only binds to activated (i.e. tyrosine autophosphorylated) EGFR. This observation led to the realization that the Src homology-2 (SH2) domains of PLCγ, GAP, and other effectors of EGFR ‘recruit’ these key proteins to the tyrosine phosphorylated tail of activated EGFR. Motivated by these observations, the Schlessinger lab took the inspired step of using a tyrosine-phosphorylated EGFR tail to probe expression libraries and thus clone numerous SH2 domain-containing proteins that are kingpins of cellular signaling, including Grb2, the p85 regulatory subunit of PI3 kinase. These now-classic studies revealed a new ‘code’ for signaling by RTKs, with specific downstream signaling molecules being recruited by RTKs through SH2/phosphotyrosine interactions. This finding had a dramatic impact on the field of growth factor receptor signaling, cancer research, and indeed cell signaling in general.
Having established this new paradigm of phosphotyrosine-mediated recruitment, Dr. Schlessinger's group discovered the key SH2/SH3 adaptor protein Grb2 and combined biochemical, genetic and biophysical approaches to understand how Grb2 links RTK activation to the Ras signaling pathway to relay information from the cell surface to the nucleus. The current concept of adaptor proteins in RTK signaling is rooted in this work, and subsequent studies in the Schlessinger laboratory have shown how complex intracellular signaling pathways are initiated by SH2 domain-mediated complex assembly.
Dr. Schlessinger’s studies have really paved the way for the development of erlotinib (Tarceva) and gefitinib (Iressa), which are EGFR inhibitors used for treating colon and lung cancers, plus imatinib (Gleevec), an Abl and c-Kit inhibitor used for treating CML and GIST patients. Dr. Schlessinger and his team at Sugen developed Sutent (SU11248), which blocks the action of PDGFR, VEGFR and c-Kit. This drug was FDA approved in 2006 for treatment of renal cancers and GIST. Sutent also appears to be effective in treatment of non-small cell lung cancer patients and a population of breast cancer patients. In a newer phase of superb studies, published in Cell in July 2007, the Schlessinger laboratory used crystallography to show how the Kit RTK (the receptor for stem cell factor) is activated. This is a key cancer target in GIST and other cancers, and these seminal data promise more novel approaches for the development of targeted cancer therapeutics.
Dr. Schlessinger received a B.Sc. degree in Chemistry and Physics in 1968 (magna cum laude) and a M.Sc. degree in Chemistry (magna cum laude) in 1970 from the Hebrew University in Jerusalem. He obtained a Ph.D. degree in biophysics from the Weizmann Institute of Science in 1974.

2010 - JOSEPH SCHLESSINGER
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