Regulation of PTHrP in Squamous Cell Carcinoma by the EGF Receptor

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DESCRIPTION (provided by applicant): Gwendolen Lorch D.V.M., M.S., seeks to become an independent scientist by studying hormone and growth factors and their role in the development and pathobiology of squamous cell carcinoma (SCC) in order to support a career in academia and biomedical research. Dr. Gwendolen Lorch is board-certified by The American College of Veterinary Dermatology (2001). Dr. Lorch is currently a NRSA postdoctoral fellow and Ph.D. student in the Department of Veterinary Biosciences at The Ohio State University. After completion of the Ph.D., Dr. Lorch will be appointed as research assistant professor in the Department of Veterinary Biosciences. Her research goal is to investigate epidermal growth factor receptor (EGFR) kinase signaling that leads to perturbed signal transduction and increased parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcemia of malignancy (HHM) in SCC of the lung. This project will have direct clinical application since the identification of deregulated oncogenic protein tyrosine kinases (PTK) leading to PTHrP overexpression will facilitate identification of potent and specific PTK inhibitors. PTHrP was initially identified as the factor responsible for HHM and is produced by all SCC. PTHrP has an important role in cancer and normal biology since it regulates cell division, differentiation, and apoptosis in addition to its function as a paracrine and endocrine hormone. Important new data from Dr. Lorch's research have revealed that EGFR signaling induces PTHrP expression in lung SCC. The overall hypothesis to be tested is that EGF ligands act in an autocrine manner with the EGFR to regulate PTHrP expression in lung SCC and induce the development of HHM. Aim 1 will measure the effects of EGFR signaling on PTHrP gene expression and mRNA stability in human SCC lines in vitro. Aim 2 will evaluate the use of EGFR-specific tyrosine kinase inhibitors on PTHrP mRNA expression, protein secretion, and development of HHM using xenograft models and lung SCC cell lines. Aim 3 will identify molecular targets downstream of the EGFR important in regulation of PTHrP and induction of HHM by measuring expressed genes in both treated and control hypercalcemic mouse models of lung SCC. Extensive preliminary data has been completed for this project. The Department of Veterinary Biosciences is a successful academic department among the six OSU Health Sciences Colleges with 30 extramurally funded researchers in endocrinology, molecular biology, experimental pathobiology, oncology, and other disciplines. The laboratories of Thomas Rosol, D.V.M., Ph.D. (sponsor) and John Foley, Ph.D. (co-sponsor) provide an excellent environment for developing the necessary skills for Dr. Lorch to become an independent scientist. The proposed research will use innovative approaches to investigate the cell surface receptor, EGFR. This receptor is present in disproportionate amounts and has abnormal activation in many cancers leading to rapid uncontrolled growth of the cells. Further, this proposal aims to identify how EGFR regulates excessive PTHrP production in lung cancer and causes life-threatening elevated calcium levels. We seek to identify specific cell signaling proteins that contribute to excessive PTHrP which may be candidate targets for design of anticancer drugs and would ultimately limit cancer cell survival, growth, and spread. The results of the research will then be translated to advance the standard of human and animal cancer care worldwide.