MGMT methylation status correlates with temozolomide-mediated radiosensitization in a panel of GBM orthotopic xenografts

Abstract

1509 Background: Lack of MGMT methylation in GBM tumors is associated with a worse outcome with combined radiation (RT) and temozolomide (TMZ) therapy, and it is unclear whether non-methylated tumors benefit from TMZ treatment. Methods: The potential benefits of concomitant or adjuvant TMZ relative to methylation status were evaluated in 10 GBM tumors established from patient samples and maintained by serial passage in mice. For each tumor line, 32 mice with established orthotopic xenografts were randomized to A) placebo, B) TMZ PO daily × 5 (120 mg/kg or 66 mg/kg, as indicated) C) RT, 2 Gy bid × 10 fx., D) combined TMZ and RT, and mice were followed until moribund. Efficacy was evaluated by regression modeling and Kaplan-Meier statistical analyses. Results: Six lines with non-methylated MGMT (GBM10, 14, 26, 28, 36, 43) and 4 with methylated MGMT (GBM8, 12, 16, 34) were evaluated, and complete results are available in 6 lines. In all tumor lines and at both dose levels, there was a significant benefit for TMZ relative to placebo (p<0.003). Both methylated tumors (GBM8 and 12) and one non-methylated tumor (GBM14) were markedly sensitive to TMZ with greater than a 50 day extension in survival with monotherapy. Individually and in a pooled analysis, there was no evidence for a synergistic interaction between TMZ and RT in the non-methylated tumors (p=0.91 for pooled analysis). In contrast, there was a striking degree of synergy in GBM12 (p<0.001) and at least additive effects of combined treatment in GBM8 (5 of 8 mice still surviving in the RT/TMZ arm). In a pooled analysis of these 2 MGMT methylated tumors, there was a trend towards synergy (p=0.11). Conclusions: TMZ treatment did not sensitize MGMT non-methylated tumors to radiation, and with one exception, these non-methylated tumors were only modestly sensitive to TMZ alone. In contrast, treatment with TMZ appears to sensitize MGMT-methylated tumors to radiation and monotherapy is associated with marked and significant benefit. [Table: see text] No significant financial relationships to disclose.