MODL-20. REDUCTION OR LOSS OF MSH6 CONFERS RESISTANCE TO TEMOZOLOMIDE IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The only intervention that has improved survival rate of GBM patients over past several decades been combining temozolomide (TMZ) with radiotherapy (RT), which increased median by ~2.5 months to where it currently stands at ~15 months. Unfortunately, all eventually die due tumor recurrence. Intrinsic or acquired resistance TMZ a significant contributing factor progression, various mechanisms have suggested, including deficiencies in DNA mismatch repair (MMR) genes such as MSH6. To test biological significance Msh6 growth immunotherapy, we generated immunocompetent genetically engineered mouse models (GEMMs) germline loss Msh6. generate tumors reduced abrogated Msh6, utilized GEMMs based on RCAS/tv-a gene transfer system combination mice exhibited heterozygous homozygous When PDGFB was overexpressed silencing Tp53 induce tumors, tumor-bearing deficient demonstrated shorter time compared wild-type mice. Our data demonstrate two weeks treatment clinically relevant dose 25 mg/kg provides advantage WT-tumor-bearing mice, while no efficacy observed either We are evaluating mechanism confers TMZ-resistance.