MERIT Award Recipient: Yosef Yarden, Ph.D.
Growth Factors and Their Receptors in Cancer: Biochemical Mechanisms and Targets for Therapy
Growth factors and their receptors are richly involved in all phases of cancer development, such as the very early clonal expansion of cells that acquired oncogenic mutations, the attraction of blood vessels to the growing tumor, and finally the invasive migration of tumor cells into lymph, as well as blood, vessels and the subsequent colonization of distant organs (metastasis). One important example is provided by the epidermal growth factor (EGF) and its family of growth promoting molecules. Many types of solid tumors abnormally produce EGF and its siblings. This mechanism, called "autocrine regulation," enables tumor cells to acquire autonomous growth and invasive properties.
Yet another mechanism allowing growth factors to contribute to tumor development is genetic aberrations, which affect growth factor receptors in various cancers. There are four such receptors (called ErbB or HER) and they are numbered 1 through 4. The prototype is the EGF receptor (HER1 or ErbB-1) and mutations within the intracellular part of this receptor are frequently found in non-small cell lung cancer and other types of tumors. Due to their potent biological activities, strategies that intercept ErbB molecules are already used to treat cancer patients. However, low therapeutic efficacy, as well as primary and secondary resistance to ErbB-targeted therapies currently limit the clinical potential of ErbB-directed drugs.
The research in our laboratory is aimed at a comprehensive understanding of growth factor action as a necessary basis for rational development of improved therapies. The MERIT award supports research that examines the potential of several experimental strategies to intercept ErbB action in model systems. One approach utilizes monoclonal antibodies to specific growth factors, which are known to be involved in certain tumors. This group of growth factors includes a newly discovered class of molecules (low-affinity ligands) we identified as potent growth stimulators, despite their relatively weak binding to target cells. An alternative approach examines engineered portions of ErbB receptors, which we develop as decoy molecules. Yet a third approach, tests the possibility that destruction of ErbB molecules in tumors will reduce cancer spread. This latter line of research focuses on the ability of molecular chaperones to degrade growth factor receptors. We plan to recruit chaperones to specific ErbB molecules by using small compounds that avidly bind and refold the target receptors. Our work is designed to identify new strategies for cancer treatment.