2019
Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors
Jackson CB, Noorbakhsh SI, Sundaram RK, Kalathil AN, Ganesa S, Jia L, Breslin H, Burgenske DM, Gilad O, Sarkaria JN, Bindra RS. Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors. Cancer Research 2019, 79: 4331-4338. PMID: 31273061, PMCID: PMC6810597, DOI: 10.1158/0008-5472.can-18-3394.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, AlkylatingAntineoplastic Combined Chemotherapy ProtocolsAtaxia Telangiectasia Mutated ProteinsCell Cycle CheckpointsCell Line, TumorCheckpoint Kinase 1DNA Breaks, Double-StrandedDNA DamageDNA Modification MethylasesDNA Repair EnzymesDrug SynergismFemaleHumansIsoxazolesMice, NudePyrazinesTemozolomideTumor Suppressor ProteinsXenograft Model Antitumor AssaysConceptsMGMT-deficient cellsPPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma
Fons NR, Sundaram RK, Breuer GA, Peng S, McLean RL, Kalathil AN, Schmidt MS, Carvalho DM, Mackay A, Jones C, Carcaboso ÁM, Nazarian J, Berens ME, Brenner C, Bindra RS. PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nature Communications 2019, 10: 3790. PMID: 31439867, PMCID: PMC6706443, DOI: 10.1038/s41467-019-11732-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBrain Stem NeoplasmsCell Line, TumorChildCytokinesDiffuse Intrinsic Pontine GliomaDNA MethylationEpigenetic RepressionFemaleGene Expression Regulation, NeoplasticHumansMiceNicotinamide PhosphoribosyltransferasePonsPrimary Cell CultureProtein Phosphatase 2CSynthetic Lethal MutationsXenograft Model Antitumor AssaysConceptsNicotinic acid phosphoribosyltransferaseSynthetic lethal interactionsNAMPT inhibitorsTumor-specific cell killingProtein phosphataseEpigenetic silencingMutant cellsKey genesCpG islandsLethal interactionsNAD biosynthesisGene expressionInhibitor sensitivityNAD metabolismOncogenic rolePediatric gliomasMutationsModel systemCell killingDriver mutationsPediatric high-grade gliomasMutant tumorsOncogenic driver mutationsNicotinamide phosphoribosyltransferase (NAMPT) inhibitionGenomeNanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma
Seo YE, Suh HW, Bahal R, Josowitz A, Zhang J, Song E, Cui J, Noorbakhsh S, Jackson C, Bu T, Piotrowski-Daspit A, Bindra R, Saltzman WM. Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma. Biomaterials 2019, 201: 87-98. PMID: 30802686, PMCID: PMC6451656, DOI: 10.1016/j.biomaterials.2019.02.016.Peer-Reviewed Original ResearchConceptsEfficient intracellular deliveryDelivery systemPeptide nucleic acidNanoparticle productsNanoparticlesIntracellular deliveryConvection-enhanced deliveryDifferent delivery systemsNucleic acidsSignificant therapeutic efficacyMiR-21 suppressionTherapeutic efficacyLocal deliveryDeliverySystemic toxicityBlock copolymersDistinct advantagesPolyglycerolMiR-21
2018
Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors
Chen EM, Quijano AR, Seo YE, Jackson C, Josowitz AD, Noorbakhsh S, Merlettini A, Sundaram RK, Focarete ML, Jiang Z, Bindra RS, Saltzman WM. Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors. Biomaterials 2018, 178: 193-203. PMID: 29936153, PMCID: PMC6082184, DOI: 10.1016/j.biomaterials.2018.06.024.Peer-Reviewed Original Research
2017
Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas
King AR, Corso CD, Chen EM, Song E, Bongiorni P, Chen Z, Sundaram RK, Bindra RS, Saltzman WM. Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas. Molecular Cancer Therapeutics 2017, 16: 1456-1469. PMID: 28566437, PMCID: PMC5545124, DOI: 10.1158/1535-7163.mct-16-0788.Peer-Reviewed Original ResearchConceptsHigh-grade gliomasPoor blood-brain barrier penetrationLocal disease progressionBlood-brain barrier penetrationEffect of radiotherapyIntrinsic pontine gliomaTreatment of glioblastomaMol Cancer TherCranial radiationDosing schedulesMultimodal treatmentIntracranial gliomasDisease progressionExtracranial tumorsPontine gliomaAggressive phenotypeRadiotherapy approachesGliomasMinimal toxicityRadiotherapyGlioblastomaBarrier penetrationTreatmentRadiosensitizerChemotherapyGBM radiosensitizers: dead in the water…or just the beginning?
Bindra RS, Chalmers AJ, Evans S, Dewhirst M. GBM radiosensitizers: dead in the water…or just the beginning? Journal Of Neuro-Oncology 2017, 134: 513-521. PMID: 28762004, DOI: 10.1007/s11060-017-2427-7.Peer-Reviewed Original ResearchConceptsPre-clinical evidenceNovel therapeutic approachesGBMs recurDevelopment of radiosensitizersClinical trialsTherapeutic approachesDNA damage response inhibitorsLocal controlPrimary siteDNA repair inhibitorsPotent agentOxidative stressRadiosensitizerRepair inhibitorsRadiosensitizationInhibitorsRadiotherapyClinicHypoxiaTrials2-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
2016
PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma
Gaudin A, Song E, King AR, Saucier-Sawyer JK, Bindra R, Desmaële D, Couvreur P, Saltzman WM. PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma. Biomaterials 2016, 105: 136-144. PMID: 27521616, PMCID: PMC5072177, DOI: 10.1016/j.biomaterials.2016.07.037.Peer-Reviewed Original ResearchConceptsConvection-enhanced deliveryGlioblastoma multiformeChemotherapeutic drugsFirst-line treatmentExtracranial solid tumorTumor-bearing animalsSurvival of animalsBrain extracellular spaceLine treatmentTumor bedIntracranial tumorsOrthotopic modelTreatment resistanceSolid tumorsGBM treatmentTherapeutic efficacyNew treatmentsTumor tissueHealthy animalsGBM prognosisFree gemcitabineMR contrast agentsNucleoside analoguesDrugsGemcitabineA single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin
Janssen A, Breuer GA, Brinkman EK, van der Meulen AI, Borden SV, van Steensel B, Bindra RS, LaRocque JR, Karpen GH. A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin. Genes & Development 2016, 30: 1645-1657. PMID: 27474442, PMCID: PMC4973294, DOI: 10.1101/gad.283028.116.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksHomologous recombinationGenome stabilityHeterochromatic DSBsEuchromatic DSBsSingle DNA double-strand breakMain DSB repair pathwaysDifferent chromatin domainsLarval imaginal discsDistinct nuclear domainsRepetitive DNA sequencesDSB repair pathwaysDouble-strand breaksChromatin contextChromatin domainsEuchromatic lociPericentromeric heterochromatinChromatin regionsHomologous chromosomesHR templateImaginal discsDSB repairDNA sequencesNuclear domainsRepair pathways
2014
Development of a novel method to create double-strand break repair fingerprints using next-generation sequencing
Soong CP, Breuer GA, Hannon RA, Kim SD, Salem AF, Wang G, Yu R, Carriero NJ, Bjornson R, Sundaram RK, Bindra RS. Development of a novel method to create double-strand break repair fingerprints using next-generation sequencing. DNA Repair 2014, 26: 44-53. PMID: 25547252, DOI: 10.1016/j.dnarep.2014.12.002.Peer-Reviewed Original ResearchConceptsHomologous recombinationNHEJ repairChromosomal lociDSB repair pathway choiceDNA double-strand break repairEndogenous chromosomal locusEfficient DNA double-strand break repairDouble-strand break repairDSB repair proteinsRepair pathway choiceDNA damaging agentsSequencing-based approachesDSB repair activityNext-generation sequencing-based approachChromatin interactionsGenomic integrityDSB repairMammalian cellsNext-generation sequencingBreak repairPathway choiceRepair proteinsReporter geneDamaging agentsRepair assays
2011
Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids
Schleifman EB, Bindra R, Leif J, del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM. Targeted Disruption of the CCR5 Gene in Human Hematopoietic Stem Cells Stimulated by Peptide Nucleic Acids. Cell Chemical Biology 2011, 18: 1189-1198. PMID: 21944757, PMCID: PMC3183429, DOI: 10.1016/j.chembiol.2011.07.010.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsHIV-1CCR5 geneHIV-1-infected individualsHIV-1 infectionGene modificationHIV-1 entryCCR5-Delta32 mutationImmune system functionStem cellsCCR5 knockoutMonths posttransplantationChemokine receptorsHuman hematopoietic stem cellsTherapeutic strategiesSubsequent engraftmentGenome modificationProtein levelsHuman cellsTargeted disruptionCCR5Peptide nucleic acidInfectionNucleic acidsCells
2009
Introduction: the evolving picture of the hypoxic tumour microenvironment.
Glazer PM, Bindra RS. Introduction: the evolving picture of the hypoxic tumour microenvironment. 2009, 9: 399-400. PMID: 19519396, DOI: 10.2174/156652409788167069.Peer-Reviewed Original Research
2005
Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis
Bindra RS, Glazer PM. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 2005, 569: 75-85. PMID: 15603753, DOI: 10.1016/j.mrfmmm.2004.03.013.Peer-Reviewed Original ResearchConceptsGenetic instabilitySuch genetic instabilityDNA repair pathwaysOxidative base damageSuch DNA lesionsGenome integrityTumor microenvironmentRepair pathwaysDNA strand breaksDNA lesionsBase damageDNA damageStrand breaksMutagenesisInduction of mutagenesisAdverse conditionsTumor progressionMicroenvironmentRecent studiesSignificant threatPotential mechanismsNumerous typesInductionPathway
2003
Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells
Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM. Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells. Molecular And Cellular Biology 2003, 23: 3265-3273. PMID: 12697826, PMCID: PMC153206, DOI: 10.1128/mcb.23.9.3265-3273.2003.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdenosine TriphosphatasesAnimalsBase Pair MismatchBeta-GalactosidaseCarrier ProteinsCell HypoxiaCells, CulturedDeferoxamineDinucleotide RepeatsDNA RepairDNA Repair EnzymesDNA-Binding ProteinsEnzyme InhibitorsFibroblastsGenes, ReporterHeLa CellsHumansHydroxamic AcidsHypoxia-Inducible Factor 1, alpha SubunitIron Chelating AgentsMethylationMiceMice, TransgenicMismatch Repair Endonuclease PMS2MutL Protein Homolog 1MutS Homolog 2 ProteinNeoplasm ProteinsNuclear ProteinsProto-Oncogene ProteinsRNA, MessengerTranscription FactorsConceptsGenetic instabilityMammalian cellsDNA mismatch repair genes MLH1Chromosomal reporter geneHistone deacetylase inhibitor trichostatin AStationary-phase mutagenesisDeacetylase inhibitor trichostatin AInhibitor trichostatin AMismatch repair genes MLH1Treatment of cellsHistone deacetylationStress signalsKey MMR proteinsReporter geneGenes MLH1Gene expressionLow oxygen tensionPMS2 levelsMMR gene expressionTrichostatin AMLH1 mRNAPotential new pathwaysDinucleotide repeatsHeterodimer partnerHypoxia-induced reduction