ATPS-50REVISITING CARBOPLATIN AS A THERAPY FOR GLIOBLASTOMA (GBM)
INTRODUCTION: The DNA alkylating agent, temozolomide (TMZ), given during and after radiotherapy (RT) improves the survival of patients with glioblastoma (GBM). TMZ is unequivocally helpful for patients with GBMs in which the DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), has been silenced by methylation of the MGMT gene promoter (i.e., 40%). For the remainder, whose GBMs express MGMT, and are therefore more resistant to TMZ, the addition of TMZ to RT adds little benefit.
... over, many who benefit initially acquire resistance to TMZ through treatment-induced mutations. The need for other therapies for GBM motivated us to re-examine carboplatin, a DNA crosslinking agent whose development for use against GBM was curtailed by the emergence of TMZ. Carboplatin is well tolerated and crosses the blood brain barrier, making it an agent of interest. METHODS: Ten brain tumor initiating cell (BTIC) lines derived from newly diagnosed or previously treated GBMs were assessed for sensitivity to carboplatin (5 or 10 ug/mL for 8 days) or TMZ (10 ug/mL for 8 days); viability was measured using the AlamarBlue assay. RESULTS: All BTICs were sensitive to carboplatin; lines derived from untreated methylated GBMs were equally sensitive to carboplatin and TMZ. Sensitivity to TMZ was only observed in BTICs that were MGMT methylated and derived from untreated patients. BTICs with an unmethylated MGMT promoter that were derived from newly diagnosed patients were resistant to TMZ, as where those from previously treated patients. CONCLUSIONS: TMZ resistance, is a major obstacle to the successful treatment of GBM; hence, the need for alternatives to TMZ. This study demonstrates that carboplatin is active against BTICs, and may be useful in situations where resistance to TMZ is seen. Although in vivo work is required to bolster the relevance of this finding, our observations suggest that carboplatin may be warrant further study for GBM.