BRAIN TUMOR ANALYSIS LAB

Division of Neuro-Oncology, Department of Neurology

Dr. G. Yancey Gillespie Professor Surgery, Microbiology, Cell Biology 1032 Tinsley Harrison Tower 1900 University Boulevard Birmingham, AL 35294 Tel: 205.934.7227 Fax: 205.934.7676 yancey@uab.edu       Bio   Research Interests Dr. Gillespie obtained B.A. (biology & chemistry), M.Sc. (cytogenetics) and Ph.D. (immunology & immunogenetics) degrees at the University of Mississippi , finishing in 1971. Following a NCI postdoctoral fellowship at the University of Kansas Medical Center, he joined the Department of Pathology. In 1975, he joined Scripps Clinic and Research Foundation in La Jolla . In 1977, he moved as Assistant Professor of Pathology to the University of North Carolina-Chapel Hill. In 1977, he transferred to the Department of Surgery, Division of Neurosurgery to direct the Brain Tumor Immunology research program. In 1986, Dr. Gillespie came to UAB as tenured Associate Professor of Surgery to direct brain tumor research efforts in the Division of Neurosurgery. He is Professor of Surgery with secondary appointments in Departments of Microbiology and Cell Biology. Dr. Gillespie is co-Director of the UAB Brain Tumor SPORE, and leader of Brain Tumor Tissue and Brain Tumor Animal Models Core Facilities.   Molecular and viral therapy of malignant primary brain tumors The main thrust of my research is to develop and test specific therapies for treatment of malignant brain tumors in adults and children. One current focus is construction of replication conditional herpes simplex viruses that are both oncolytic for glioma cells and express foreign therapeutic genes. Gene transfer includes both pro-drug converting enzymes and cytokines under different promoter systems. Pro-drug enzyme systems currently being studied are cytosine deaminase (CD) alone or as a fusion protein with uracil phosphoribosyl transferase (UPRT) and purine nucleoside phosphorylase (PNP). A second focus involves studies with the CD and CDUPRT systems in both replication incompetent adenovirus and conditionally replication competent adenovirus. Adenoviruses targeted to cell surface receptors on glioma cells are being constructed to provide tumor specificity. Cytokines expressed from replication competent HSV that are being studied include TNF a , IL-2, IL-4, IL-5, IL-10, IL12, IL-16. These systems are validated by in vitro assays first before being advanced to safety and efficacy assessment in a variety of murine models of intracranial malignant gliomas. These models include transplantable intracranial gliomas of human origin (in immunocompromised scid or nude mice) or mouse origin (in syngeneic conventional mice). We also have acquired 2 transgenic glioma mouse models and use high-field strength (8.5T) magnetic resonance imaging to detect and monitor tumor growth in transgenic mice. One intriguing observation is the fact that many of these viral oncolytic and transgene therapies are markedly enhanced by modest doses of whole brain irradiation. This phenomenon is being studied at the cellular and molecular levels to determine how it can be best employed as a therapeutic strategy. Vectors that are to be advanced to clinical trials are tested for neurotoxicity in non-human primates. Finally, small peptides that exert an anti-angiogenic effect on tumor neovasculature or that induce apoptosis in human glioma cells are being studied as therapeutic agents in vitro and in animal models of malignant brain tumors.   Virology, Neurobiology, Molecular genetics and disease   Representative Publications Gillespie GY, Soroceanu L, Manning TJ Jr, Gladson CL, Rosenfeld SS. Glioma migration can be blocked by nontoxic inhibitors of myosin II. Cancer Res. 1999 May 1;59(9):2076-82. Markert JM, Gillespie GY, Weichselbaum RR, Roizman B, Whitley RJ . Genetically engineered HSV in the treatment of glioma: a review. Rev Med Virol. 2000 Jan-Feb;10(1):17-30. Review. Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY. Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. Cancer Res. 2002 Feb 1;62(3):773-80. Tsai JC, Teng LJ, Chen CT, Hong TM, Goldman CK, Gillespie GY. Protein kinase C mediates induced secretion of vascular endothelial growth factor by human glioma cells. Biochem Biophys Res Commun. 2003 Oct 3;309(4):952-60. Shah AC, Benos D, Gillespie GY, Markert JM . Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol. 2003 Dec;65(3):203-26.  Secrist, J.A., Parker, W.B., Allan, P.W., Bennett, L.L., Waud, W.R., Truss, J.W., Fowler, A.T., Montgomery, J.A., Ealick, S.E., Wells, A.H., Gillespie, G.Y. , Gadi, V.K., Sorscher, E.J. Gene therapy of cancer: activation of nucleoside prodrugs with E. coli purine nucleoside phosphorylase. Nucleosides Nucleotides . 18: 745-757, 1999. Bradley, J.D., Kataoka, Y., Advani, S., Chung, S.M., Arani, R.B., Gillespie, G.Y. , Whitley, R.J., Markert, J.M., Roizman, B. and Weichselbaum, R.R. Ionizing radiation improves survival in mice bearing intracranial high grade gliomas injected with genetically modified herpes simplex virus. Clinical Cancer Res. 5: 1517-1522 , 1999.