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Brain Tumor Research Laboratory

Gregory W. Canute, MD, Associate Professor

Molecular Genetics of Glioblastoma Multiforme (GBM)

Dr. Canute's research is focused on examining the molecular genetics of glioblastoma multiforme (GBM) with the goal of developing new therapeutic agents against this malignant brain tumor. The epidermal growth factor receptor (EGFR) has been a major focus since 1993. Some of the current research interests include using the recently FDA approved monoclonal antibody against EGFR, cetuximab (Erbitux,C225), a monoclonal antibody against EGFR and tyrosine kinase inhibitors that target the EGFR signaling pathway. Previously using hydroxyurea we demonstrated decreased cell proliferation through the EGFR pathway by inhibiting the ribonucleotide reductase enzyme. Cetuximab also attacks the EGFR pathway by blocking access of essential growth.

factors to the cells. We demonstrated in recently published work that cetuximab increased apoptosis and decreased cell proliferation in EGFR-amplified GBM cells in vitro. When cetuximab was given to mice harboring GBM intracranially or in the flank it significantly increased their survival. Cetuximab has also been tested in our laboratory in combination with standard radiation and chemotherapy. These experiments resulted in additive tumor cell death when combining cetuximab with either radiation or chemotherapy both in vitro and in vivo.

New small molecule tyrosine kinase inhibitors against EGFR have recently gained use in clinical oncology. Some of these have been tested against our EGFR amplified and unamplified GBM. While these agents are very cytotoxic against EGFR amplified GBM, they are cytotoxic to a much lesser degree against unamplified GBM via a different mechanism. We are planning preclinical testing of new tyrosine kinase inhibitors against our GBM in the near future.

Efforts to understand the cellular requirements that make GBM sensitive to EGFR inhibition by either Cetuximab or tyrosine kinase inhibitors are underway. Analysis of DNA copy number and mRNA expression by gene array analysis is in progress for tyrosine receptor kinase second messengers and apoptosis intermediates. Protein analysis of activated and inactivated second messengers is also in progress. These results should help us determine the cellular expression requirements for sensitivity to EGFR inhibition in GBM.