Scientific Advisory Board

• Daniel Anderson, Ph.D.
• Alan Colman, Ph.D.
• Hongkui Deng, Ph.D.
• Sheng Ding, Ph.D.
• Rudolf Jaenisch, M.D.
• Jeffrey Karp, Ph.D.
• Robert Langer, Sc.D.
• Douglas A. Melton, Ph.D.
• Roy Ogle, Ph.D.
• Thomas Roberts, Ph.D.
• Lee Rubin, Ph.D.
• Bob Weinberg, Ph.D.
• Leonard Zon, M.D.

Thomas Roberts, Ph.D.

Signaling mechanisms and cancer

Professor of Pathology, Harvard Medical School Chair, Department of Cancer Biology, Dana-Farber Cancer Institute

Dr. Roberts received his PhD in 1976 from Harvard University, where he also completed a postdoctoral fellowship. In 1981, he joined the DFCI faculty. He has played a seminal role in developing the techniques used to study signaling downstream from tyrosine kinases. Using viral oncogenes as a base, his laboratory has pioneered research on the two key signaling components: PI3 kinase and Raf-1.

Research in the Roberts laboratory is centered on the molecular mechanisms of signal transduction in response to activated tyrosine kinases. They pioneered structure/function studies on tyrosine kinases showing how tyrosine kinases such as pp60c-src are themselves regulated by tyrosine phosphorylation. The first definitive work on PI3'kinase was done by this lab in collaboration with that of Cantley and Schaffhausen. Similarly our lab first showed that the serine threonine kinase Raf-1 was regulated by mitogens and then helped to elucidate the pathway from p21ras to Raf to MAP kinases. More recently they first characterized the novel binding site used by the SHC protooncogene product to bind to receptors, and pointed out the interaction of the 14-3-3 molecules with key signal transducers. Finally they and their collaborators in the DeCaprio and Schaffhausen labs have showed how virus-encoded tumor antigens use molecular chaperones to direct the ubiquitin dependent degradation of phosphorylated forms of cell cycle control proteins. Currently they are working to clone and characterize new signaling molecules. The lab specializes in developing technologies for the study of signaling. These include the first synthetic gene for a tyrosine kinase (lck), the most widely used antiphosphotyrosine antibody, and the use of the zebrafish system for studying the role of signaling molecules in development.

Through the process of signal transduction, cells communicate what is happening on their surfaces to the regulatory machinery inside. This process is facilitated by a class of enzymes called kinases, which help activate specific genes in the long strands of DNA in a cell's nucleus. An overactive kinase can lead to an overactive gene and, ultimately, to cancer. Dr. Roberts' laboratory is researching the role of these catalysts of cell growth and division and has discovered how several work. Their discoveries have become the basis of new drugs that target the actions of specific kinases. This class of drugs, called kinase inhibitors, offers extraordinary hope for the future of cancer care.

Research in the laboratory currently focuses on three areas. One is how particular kinases are involved in cancer. For instance, the kinase termed Akt blocks the orderly process of cell death, called apoptosis. Thus, inhibiting Akt should lead to tumor cell death. We are also exploring new ways to measure kinase activity in tumors. Every tumor is unique, with its own pattern of activated kinases. Because there are more than 1000 different kinases in a given tumor, it is important to find which ones are activated so that we know which ones to inhibit. Finally, our laboratory is developing model systems to study kinases in tumors using organisms as diverse as zebrafish and mice.

Once kinases have been pinpointed, his laboratory develops the techniques and technology that allow pharmaceutical companies to make new drugs that target them. They supply the company with the reagents necessary to test the effect of drugs on the action of tyrosine kinases. In addition, DFCI scientists have developed the means to make kinases for testing. This collaboration has led to the creation of several new drugs. In particular, the drug Gleevec has been approved by the FDA against chronic myeloid leukemia (CML). Gleevec has proved to be nontoxic and effective in stopping growth of the tumor cells over other kinase inhibitors. They are also initiating phase I trials targeting other tumors, such as glioblastoma, an aggressive brain tumor.