2021
Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair
Dow J, Krysztofiak A, Liu Y, Colon-Rios DA, Rogers FA, Glazer PM. Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair. Molecular Cancer Research 2021, 19: 2057-2067. PMID: 34535560, PMCID: PMC8642278, DOI: 10.1158/1541-7786.mcr-21-0456.Peer-Reviewed Original ResearchConceptsHistone deacetylase inhibitor vorinostatPatient-derived tumor xenograftsHomology-directed repairIsocitrate dehydrogenase 1/2 mutationsHistone deacetylase inhibitionIDH1 mutant cellsGreater cell deathHDACi treatmentInhibitor vorinostatTumor xenograftsDeacetylase inhibitionIDH1/2 mutationsPotential biomarkersSpecific cancersMutant cancersCancerCancer cellsDNA repair defectsMalignancyVorinostatDNA double-strand breaksGliomasHistone hypermethylationCell deathPARPiClinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas
Eder JP, Doroshow DB, T. K, Keedy VL, Sklar JS, Glazer P, Bindra R, Shapiro GI. Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas. JCO Precision Oncology 2021, 5: 466-472. PMID: 34994649, PMCID: PMC9848565, DOI: 10.1200/po.20.00247.Peer-Reviewed Original ResearchConceptsPulmonary epithelioid hemangioendotheliomaStable diseaseEpithelioid hemangioendotheliomaClinical benefitClinical benefit rateOpen-label studyPrimary end pointPoly (ADP-ribose) polymerase inhibitionDefective homologous recombination (HR) repairMesenchymal sarcomaObjective responsePartial responseClinical efficacyPatient populationBenefit rateCombination trialsPatientsSolid tumorsIDH1/2-mutant tumorsIDH1/2 mutationsPARP inhibitorsEnd pointPARP inhibitionTumorsOlaparib
2017
Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors.
Bindra R, Sulkowski P, Corso C, Glazer P, Shuch B. Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors. Journal Of Clinical Oncology 2017, 35: 11586-11586. DOI: 10.1200/jco.2017.35.15_suppl.11586.Peer-Reviewed Original ResearchAcute myeloid leukemiaMulti-center phase II trialIDH1/2 mutationsPARP inhibitorsMutant IDH1/2 inhibitorsPhase II trialEfficacy of olaparibPoly (ADP-ribose) polymerase (PARP) inhibitorsRelated gene mutationsHomologous recombination defectsII trialIDH1/2 inhibitorsMyeloid leukemiaIsocitrate dehydrogenase 1Therapeutic strategiesPathologic processesSmall molecule inhibitorsIDH1/2-mutant tumorsSmall molecule inhibitionTumor progressionDNA repair inhibitorsPolymerase inhibitorsModern oncologyTumor cellsKey mediator2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science Translational Medicine 2017, 9 PMID: 28148839, PMCID: PMC5435119, DOI: 10.1126/scitranslmed.aal2463.Peer-Reviewed Original ResearchConceptsIsocitrate dehydrogenase 1PARP inhibitor sensitivityPossible therapeutic strategiesHomologous recombination defectsTherapeutic strategiesTumor xenograftsInhibitor sensitivityPathologic processesSmall molecule inhibitorsIDH1/2 mutationsTumor progressionIDH2 mutationsMutant IDHPolymerase inhibitorsGlioma cellsTumor cellsHR deficiencyPARP inhibitionIDH mutationsInhibitory effectDehydrogenase 1Neomorphic activityMutant IDH1 enzymeDependent dioxygenasesMutant cells