| The most common type of primary brain tumor is glioblastoma multiforme (GBM). Life expectancy for patients with GBM is less than one year and 5-year survival is 1%, and there has been no significant change in survival in more than 20 years. Chemotherapy has improved survival with limited success. The most common chemotherapeutic agent used for GBM is BCNU. We performed a detailed and systematic study of the mechanism of BCNU resistance at the molecular level.; In the First Specific Aim, we demonstrated a correlation between in vitro chemoresistance and clinical response to BCNU chemotherapy. 29% of patients were resistant to BCNU at the time of diagnosis. Extreme Drug Resistance (EDR) tumors had a statistically significant 45% decrease in mean survival of 4.9 +/- 5.2 months, compared to 10.8 +/- 5.7 months for the non-EDR group. Kaplan-Meier analysis confirmed significant differences in survival between EDR and non-EDR groups (log-rank test, P = 0.029). There were no differences in mean age, RPA class, % gross total resection, or post-operative radiation, to account for the differences in survival, other than EDR vs. Non-EDR.; In the Second Specific Aim, we identified a 301-gene molecular signature for BCNU chemoresistance in human gliomas. 6 gene expression profiles were confirmed by quantitative real-time PCR: Caspase 1, Hepatocyte Growth Factor (HGF), Heat Shock Protein 105, Mitogen Actived Protein Kinase Kinase Kinase, NADPH Dehydrogenase, quinine 1, and Transforming Growth Factor 1 beta.; In the Third Specific Aim, we were able to predict response in 20 glioma patients with 95% accuracy, based on a 301-gene molecular signature for BNCU resistance. Single-stranded interference RNA (siRNA) was utilized for prospective HGF gene inactivation in vitro to assess for functional consequence in the U251 glioma cell line. |
