John Mendelsohn, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Joseph Bolen, Ph.D., Bristol Myers Squibb, Princeton, NJ
Rik Derynck, Ph.D., University of California, San Francisco
John Hancock, MD, Ph.D., Onyx Pharmaceuticals, Richmond, CA
David C. Heimbrook, Ph.D., Merck Research Laboratories, West Point, PA
Lee J. Helman, MD, National Cancer Institute, Bethesda, MD
Benjamin G. Neel, MD, Ph.D., Harvard Medical School, Boston, MA
Sarah Parsons, Ph.D., University of Virginia, Charlottesville, VA
Neal Rosen, MD, Ph.D., Memorial Sloan-Kettering Cancer Center, New York, NY
Edward A. Sausville, MD, National Cancer Institute, Bethesda, MD
Nicholas Tonks, Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Yosef Yarden, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Layout and Goals
- Receptors and Growth Factors
- Signal Transduction I
- Signal Transduction II
- Human Cancer
Dr. Mendelsohn planned the Forum on “Growth Factors” with emphasis on those that mediate signal transduction through protein tyrosine kinases. His hopes were for a “truly creative think tank.” In July 1996, Mendelsohn assumed the presidency of M. D. Anderson, becoming only the third full-time president of the Houston-based institution.
This year’s topic was growth factors. The central theme of the meeting was the mechanisms by which growth factors regulate cells through signal transduction pathways. During the past two decades, it has been learned that cells (including most cancer cells) cannot grow in a purely autonomous fashion. Instead, their capacity to grow and multiply is regulated by growth factors. These are small polypeptide molecules which bind to highly specific receptors on the cell surface, the way a key fits into a lock. In the presence of appropriate growth factors, cells activate the biochemical pathways which enable them to replicate DNA and undergo mitotic cell division.
Research on the nature of the biochemical steps that can carry a signal from receptors in the cell surface membrane to the genes that control cell function has opened up an exciting area of investigation with tremendous clinical potential. A series of biochemical steps are involved in this transfer of information, creating what is known as signal transduction pathways. In parallel with discovering the individual ‘players’ in these pathways, there has been a great deal of activity attempting to develop specific pharmacologic agents that can block the various steps, thereby regulating cancer cell proliferation.
The assembled group of investigators represented a wide variety of disciplines. Each of the presentations stimulated questions and discussion, forcing us to convene far past the planned hours.
Entry into signal transduction is initiated by the biding of a growth factor to its receptor. Rik Derynck presented information suggesting the transforming growth factor-the epidermal growth factor and as a receptor molecule in its own right. This raised the interesting possibility that a molecule can serve that cells use to regulate activities such as cell growth. Growth factor receptors in cell surface membranes contain an intrinsic enzyme activity called a tyrosine kinase, which is able to phosphorylate proteins on their tyrosine residues. Many other kinases are found inside the cell, and are activated as a secondary step when growth factors bind to receptors on the cell surface. Dr. Sarah Parsons described experiments which explain the mechanism of activating the best understood of these kinases, the c-src tyrosine kinase. Dr. Joseph Bolen expanded on this theme, outlining a long list of intracellular tyrosine kinases that seem to have developed specialized activities in particular cells for example in lymphocytes. There has been a great deal of progress defining the structures of these kinases and the mechanisms by which they act in the signal transduction pathway.
One of the main targets of the proteins that are phosphorylated by kinases is an important oncoprotein known as ras. Dr. Neal Rosen presented interesting studies with colon carcinoma lines which demonstrate the way that ras interdigitates with other signaling molecules. Screening tests have demonstrated that ras is abnormal because of mutations in about half of the colon cancer cells examined. Pathways have been identified which could accomplish similar biochemical consequences in situations where the ras protein is normal. Dr. John Hancock presented exciting information showing the capacity of new drugs to block the function of ras. Clinical trials are planned with these inhibitory agents.
Other potential therapeutic approaches were also considered. Dr. David Heimbrock described compounds which act on the Rb protein, another regulator of cell cycle division, and other drugs which block an important regulatory kinase known as PI-3 kinase. Dr. Ed Sausville presented possible therapeutic attacks at a number of levels of the signal transduction pathway. The herbimycins and small synthetic chemicals known as tyrphostins can directly block the tyrosine kinases associated with receptors or free in the cell. Other molecules such as flavines and aphidocholine block steps in the growth cycle of cells which also may be exploitable in the treatment of cancer.
In these presentations, there was emphasis on the phosphorylation of proteins as key regulatory steps. Drs. Benjamin Neel and Nicholas Tonks provided important evidence that phosphorylation in itself is regulated, by enzymes known as phosphatases. These phosphatases can directly counteract the activity of kineses, by dephosphorylating proteins that have been activated by kinases. The fine tuning of the “yin-yang” balance in phosphorylation is only beginning to be understood, but again, provides a focus for pharmacologic intervention in the future.
At the end of the meeting there was a great deal of enthusiasm about the knowledge that had developed, explaining the mechanisms by which the binding of growth factors to receptors on the cell surface can activate signaling pathways that regulate cell proliferation. These discoveries, in turn, provide many leads towards new chemical agents with potential therapeutic efficacy, and some of these have already moved into clinical trials. This is yet another example of how fundamental scientific research is leading to new advances in health care, specifically in the area of cancer treatment.