Featured Publications
Mechanism-based design of agents that selectively target drug-resistant glioma
Lin K, Gueble SE, Sundaram RK, Huseman ED, Bindra RS, Herzon SB. Mechanism-based design of agents that selectively target drug-resistant glioma. Science 2022, 377: 502-511. PMID: 35901163, PMCID: PMC9502022, DOI: 10.1126/science.abn7570.Peer-Reviewed Original Research
2024
Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers
Huseman E, Lo A, Fedorova O, Elia J, Gueble S, Lin K, Sundaram R, Oh J, Liu J, Menges F, Rees M, Ronan M, Roth J, Batista V, Crawford J, Pyle A, Bindra R, Herzon S. Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers. Journal Of The American Chemical Society 2024, 146: 18241-18252. PMID: 38815248, PMCID: PMC11409917, DOI: 10.1021/jacs.3c06483.Peer-Reviewed Original ResearchDNA repair capacityDifferential DNA repair capacityDNA interstrand cross-linksRepair capacityInterstrand cross-linksDisplacement of fluorideDNA repairCross-linkingAberrant DNA repairLesionsHealthy tissueBrain cancerRing openingHealthy cellsMGMTSelective chemotherapyGenotoxic agentsTumorChemical DNA modificationsCancerMultistep processRepair
2022
The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors
Gueble SE, Vasquez JC, Bindra RS. The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors. Current Treatment Options In Oncology 2022, 23: 1566-1589. PMID: 36242713, DOI: 10.1007/s11864-022-01024-5.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHomologous recombination deficiencyPrimary CNS tumorsCNS tumorsClinical trialsPARP inhibitorsPreclinical evidencePrimary malignant central nervous system tumorMalignant central nervous system tumorsCentral nervous system tumorsImmune checkpoint inhibitorsStandard treatment modalityInitial clinical trialsEarly phase trialsNervous system tumorsCentral nervous tumorsExtracranial cancerCheckpoint inhibitorsDevastating malignancyStandard therapyOngoing trialsCombination therapyTreatment optionsTreatment modalitiesSystem tumorsPhase trialsOncometabolites as Regulators of DNA Damage Response and Repair
Gueble SE, Bindra RS. Oncometabolites as Regulators of DNA Damage Response and Repair. Seminars In Radiation Oncology 2022, 32: 82-94. PMID: 34861999, DOI: 10.1016/j.semradonc.2021.09.004.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDNA damage responseDamage responseDDR defectsMultiple DNA repair pathwaysSynthetic lethal interactionsDNA repair pathwaysRepair pathwaysLethal interactionsDiverse mechanismsOncometaboliteCancer therapyCertain cancersNew mechanismTherapeutic strategiesSmall intermediatesBiologyRegulatorPathwayMechanismRepairDDRMetabolismDysregulationDefectsResponse
2019
Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51
Kaplan AR, Gueble SE, Liu Y, Oeck S, Kim H, Yun Z, Glazer PM. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Science Translational Medicine 2019, 11 PMID: 31092693, PMCID: PMC6626544, DOI: 10.1126/scitranslmed.aav4508.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBRCA1 ProteinBRCA2 ProteinCell Line, TumorDNA RepairDown-RegulationE2F4 Transcription FactorFemaleGene Expression Regulation, NeoplasticHumansMice, NudePoly(ADP-ribose) Polymerase InhibitorsQuinazolinesRad51 RecombinaseReceptors, Platelet-Derived Growth FactorTumor HypoxiaVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsHomology-directed DNA repairDNA repairE2F transcription factor 4Protein phosphatase 2ATranscription factor 4DNA repair inhibitorsPhosphatase 2ARAD51 recombinaseTranscriptional corepressorMouse tumor xenograftsSynthetic lethalityGene expressionRB2/Mouse bone marrowGrowth factor receptor inhibitionRepair inhibitorsUnknown mechanismPlatelet-derived growth factor receptor inhibitionFactor 4Human tumorsInhibitor olaparibPARP inhibitorsMutationsCombination of cediranibCancer therapy
2018
PTEN Regulates Non-Homologous End Joining by Epigenetic Induction of NHEJ1/XLF
Sulkowski PL, Scanlon SE, Oeck S, Glazer PM. PTEN Regulates Non-Homologous End Joining by Epigenetic Induction of NHEJ1/XLF. Molecular Cancer Research 2018, 16: molcanres.0581.2017. PMID: 29739874, PMCID: PMC6072556, DOI: 10.1158/1541-7786.mcr-17-0581.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksKey DNA repair pathwaysCytotoxic DNA lesionsXRCC4-like factorPatient-derived melanomasDNA repair pathwaysDouble-strand breaksNovel regulatory roleTumor suppressor geneSuppression of PTENHistone acetyltransferasesDSB repairGenomic analysisNHEJ defectsNonhomologous endRepair pathwaysGene promoterNovel functionRegulatory acetylationNHEJ deficiencyDNA lesionsRegulatory roleSuppressor geneNHEJ DSB repairNHEJ
2017
Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma
Scanlon SE, Hegan DC, Sulkowski PL, Glazer PM. Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget 2017, 9: 4647-4660. PMID: 29435132, PMCID: PMC5797003, DOI: 10.18632/oncotarget.23470.Peer-Reviewed Original ResearchDouble-strand break repairDNA double-strand break repairBreak repairHomologous recombinationHomology-dependent DNA double-strand break repairGene expressionHuman clear cell renal carcinomaHuman renal cell carcinomaVon Hippel-Lindau (VHL) tumor suppressor geneDNA double-strand breaksDNA repair gene expressionHr gene expressionRadiation-induced DNA double-strand breaksImpaired DNA double-strand break repairPro-growth stateDouble-strand breaksDNA repair genesRepair gene expressionDNA repair defectsTumor suppressor genePARP inhibitor sensitivityRenal cancer cellsTranscriptional reprogrammingGene repressionRenal carcinoma samplesAnti-tumor Activity of miniPEG-γ-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy
Gupta A, Quijano E, Liu Y, Bahal R, Scanlon SE, Song E, Hsieh WC, Braddock DE, Ly DH, Saltzman WM, Glazer PM. Anti-tumor Activity of miniPEG-γ-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy. Molecular Therapy - Nucleic Acids 2017, 9: 111-119. PMID: 29246289, PMCID: PMC5633812, DOI: 10.1016/j.omtn.2017.09.001.Peer-Reviewed Original ResearchMiR-210Human tumor xenograftsAnti-tumor activityHistopathological analysisTherapeutic approachesMicroRNA-210Tumor xenograftsOncogenic miRTumor cellsHypoxic cellsAnticancer therapyHuman cancersCell proliferationCancer therapyConsiderable necrosisSignificant delayTherapyOncogenic microRNAsInhibition strategiesCellsMicroRNAsFibrosisXenograftsNecrosisTumorsNickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells
Scanlon SE, Scanlon CD, Hegan DC, Sulkowski PL, Glazer PM. Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis 2017, 38: 627-637. PMID: 28472268, PMCID: PMC5862357, DOI: 10.1093/carcin/bgx038.Peer-Reviewed Original ResearchConceptsHomology-dependent DNA double-strand break repairDNA repair pathwaysRepair pathwaysHigh-fidelity DNA repair pathwayDNA double-strand break repairMismatch repairDouble-strand break repairDNA double-strand breaksGlobal transcriptional patternsDNA repair proteinsRadiation-induced DNA double-strand breaksDouble-strand breaksTranscriptional repressionDirect DNA damageHost-cell reactivation assayEpigenetic remodelingTranscriptional patternsTranscriptional changesBreak repairDNA mutagenesisGenomic instabilityRepair proteinsHeavy metals nickelLung cellsTumor growth2-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
2015
Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment
Scanlon SE, Glazer PM. Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair 2015, 32: 180-189. PMID: 25956861, PMCID: PMC4522377, DOI: 10.1016/j.dnarep.2015.04.030.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDNA repair pathwaysRepair pathwaysDNA repairCertain DNA repair genesMost DNA repair pathwaysDNA double-strand break repairDouble-strand break repairPost-translational modificationsNucleotide excision repairDNA repair genesTumor suppressor geneMultifaceted controlTranslational downregulationEpigenetic levelBreak repairMutator phenotypeCellular consequencesGenomic instabilityExcision repairHypoxic cancer cellsSuppressor geneIntra-tumor heterogeneityMismatch repairPersistent silencingDNA damage
2014
Hypoxic Stress Facilitates Acute Activation and Chronic Downregulation of Fanconi Anemia Proteins
Scanlon SE, Glazer PM. Hypoxic Stress Facilitates Acute Activation and Chronic Downregulation of Fanconi Anemia Proteins. Molecular Cancer Research 2014, 12: 1016-1028. PMID: 24688021, PMCID: PMC4101147, DOI: 10.1158/1541-7786.mcr-13-0628.Peer-Reviewed Original ResearchConceptsFanconi anemia proteinsDNA repair pathwaysFA pathwayGenomic instabilityRepair pathwaysUbiquitination of FANCD2Intact FA pathwayATR-dependent mannerFA pathway activationAccumulation of γH2AXGenome integrityReplication stressTranscriptional repressionHypoxic conditionsFANCD2Cell survivalDNA damageHypoxic downregulationProtein downregulationHypoxic stressFANCIPathway activationPathwayKey membersCritical role
2013
Hypoxia and DNA repair.
Glazer PM, Hegan DC, Lu Y, Czochor J, Scanlon SE. Hypoxia and DNA repair. The Yale Journal Of Biology And Medicine 2013, 86: 443-51. PMID: 24348208, PMCID: PMC3848098.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDNA repairHomology-dependent repairDNA repair pathwaysNucleotide excision repairDNA mismatch repairGenomic integrityDependent repairCell physiologyRepair pathwaysExcision repairHypoxic cancer cellsCell metabolismGenetic instabilityMismatch repairInduction of angiogenesisCancer progressionCell growthCancer cellsNeoplastic developmentRepairSolid tumorsKey componentHypoxiaProfound changesApoptosisOxidative Stress in Mammalian Cells Impinges on the Cysteines Redox State of Human XRCC3 Protein and on Its Cellular Localization
Girard P, Graindorge D, Smirnova V, Rigolet P, Francesconi S, Scanlon S, Sage E. Oxidative Stress in Mammalian Cells Impinges on the Cysteines Redox State of Human XRCC3 Protein and on Its Cellular Localization. PLOS ONE 2013, 8: e75751. PMID: 24116071, PMCID: PMC3793007, DOI: 10.1371/journal.pone.0075751.Peer-Reviewed Original ResearchConceptsHomologous recombinationSensitivity to camptothecinCysteine to serineInhibition of DNA replicationCysteine redox stateExposure to camptothecinCellular reducing systemsTargets of ROSIn silico predictionMutant proteinsRAD51 paralogsGenome stabilitySubcellular localizationNon-reducing SDS-PAGEDNA replicationIncreased electrophoretic mobilityMutated proteinChromatin fractionHR pathwayCamptothecin treatmentCysteine residuesInduce DNA damageHuman cellsCellular localizationCHO cellsGenetic Instability Induced by Hypoxic Stress
Scanlon SE, Glazer PM. (2013). Genetic Instability Induced by Hypoxic Stress. In: Mittelman, D. (eds) Stress-Induced Mutagenesis. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6280-4_8Chapters