The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma
McCord M, Sears T, Wang W, Chaliparambil R, An S, Sarkaria J, James C, Ruggeri B, Gueble S, Bindra R, Horbinski C. The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma. Neuro-Oncology 2024, noae257. PMID: 39658092, DOI: 10.1093/neuonc/noae257.Peer-Reviewed Original ResearchMedian survival of miceSurvival of miceMedian survivalIDH wild-type glioblastomaO-6-methylguanine-DNA methyltransferaseExposure to temozolomideAcquired resistance to TMZWild-type glioblastomaPatient-derived xenograftsSensitivity to temozolomidePatient-derived modelsResistance to temozolomideLN229 glioma cellsPatient-derived glioblastomaRecurrent tumorsMGMT deficiencyFractionated RTTemozolomideLow dosesImprove outcomesGlioblastomaEnzyme deficiencyMismatch repairGlioma cellsGBM12EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS
McCord M, Wang W, An S, Sears T, Sarkaria J, James C, Ruggieri B, Bindra R, Horbinski C. EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS. Neuro-Oncology 2024, 26: viii241-viii241. PMCID: PMC11553709, DOI: 10.1093/neuonc/noae165.0954.Peer-Reviewed Original ResearchPatient-derived xenograftsDNA inter-strand cross-linksMismatch repairDNA mismatch repairGlioblastoma cell linesBase mismatchesShRNA knockdownGlioblastoma patient-derived xenograftsMGMT deficiencyMGMT-deficient cellsDNA damageInter-strand cross-linksDNAMMR-deficient tumor cellsCell linesPatient-derived xenograft modelsComplementary in vitro studiesAlkylating agent temozolomideMMR genesVehicle control miceDays post-engraftmentApoptosisMismatch repair mutationsDNA basesResistance to temozolomideO6-Guanine Targeting Novel DNA Cross-Linker and ATR Inhibitor Combination for MGMT-Silenced IDH1/2 Mutant Acute Myeloid Leukemia
Bhardwaj P, Sundaram R, Friedman S, Baassiri A, Matthews M, VanOudenhove J, Gueble S, Halene S, Bindra R. O6-Guanine Targeting Novel DNA Cross-Linker and ATR Inhibitor Combination for MGMT-Silenced IDH1/2 Mutant Acute Myeloid Leukemia. Blood 2024, 144: 6130. DOI: 10.1182/blood-2024-210621.Peer-Reviewed Original ResearchAML patient samplesHematologic adverse effectsMGMT promoter hypermethylationPatient-derived xenograftsDe novoMismatch repairO6 position of guaninePromoter hypermethylationMyelodysplastic syndromeRNA-seq analysisMyeloid leukemiaATR inhibitorsDNA repair proteinsClinical trialsSelection of mutationsFunctional mismatch repairPatient samplesMutant acute myeloid leukemiaBiomarker-targeted therapiesCell line pairsAlkylation DNA damageMutant IDH1/2 inhibitorsRNA-seqCases of AMLMGMT promoter methylation