2020
Oncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, King MC, Bindra RS, Glazer PM. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 2020, 582: 586-591. PMID: 32494005, PMCID: PMC7319896, DOI: 10.1038/s41586-020-2363-0.Peer-Reviewed Original ResearchConceptsDNA repairDNA breaksFumarate hydrataseDownstream repair factorsHistone 3 lysine 9Homology-dependent repairPoly (ADP-ribose) polymeraseRecruitment of TIP60Deregulation of metabolismChromatin signalingSuccinate dehydrogenase genesGenome integrityLysine 9Repair factorsDehydrogenase geneEnd resectionIsocitrate dehydrogenase 1Aberrant hypermethylationMechanistic basisSomatic mutationsDehydrogenase 1GenesHuman malignanciesProper executionMutations
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
Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma
Xu Y, Taylor P, Andrade J, Ueberheide B, Shuch B, Glazer PM, Bindra RS, Moran MF, Linehan WM, Neel BG. Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma. Cancer Research 2018, 78: 6539-6548. PMID: 30297534, PMCID: PMC6279512, DOI: 10.1158/0008-5472.can-18-0901.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersCell Line, TumorFumarate HydrataseGerm-Line MutationHumansLeiomyomatosisMetabolomeMetabolomicsModels, BiologicalNeoplastic Syndromes, HereditaryOxidation-ReductionPhosphorylationProtein BindingProtein Tyrosine Phosphatase, Non-Receptor Type 12Proto-Oncogene Proteins c-ablReactive Oxygen SpeciesSkin NeoplasmsUterine NeoplasmsKrebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair
Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S, Niger M, Boeke M, Ueno D, Kalathil AN, Bao X, Li J, Shuch B, Bindra RS, Glazer PM. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nature Genetics 2018, 50: 1086-1092. PMID: 30013182, PMCID: PMC6072579, DOI: 10.1038/s41588-018-0170-4.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksPGL/PCCDNA repair deficiency syndromeHomologous recombination DNA repair pathwayDNA repair pathwaysDouble-strand breaksHomologous recombination DNA repairSynthetic lethal targetingGenomic integrityDNA repairFumarate hydrataseMechanistic basisCancer predispositionFunction mutationsGermline lossKrebs cycleSuccinate dehydrogenaseHereditary paragangliomaRespectively1–3Ribose polymerase inhibitorsHereditary leiomyomatosisHereditary cancer syndromesCancer syndromesTumor cellsPolymerase inhibitors
2017
DNA polymerase beta participates in DNA End-joining
Ray S, Breuer G, DeVeaux M, Zelterman D, Bindra R, Sweasy JB. DNA polymerase beta participates in DNA End-joining. Nucleic Acids Research 2017, 46: 242-255. PMID: 29161447, PMCID: PMC5758893, DOI: 10.1093/nar/gkx1147.Peer-Reviewed Original ResearchConceptsDouble-strand breaksAlternative NHEJHomologous recombinationDNA polymerasePol βX-family DNA polymerasesFamily DNA polymerasesDNA polymerase betaDNA pol βDeleterious lesionsDNA endsGenomic instabilityNHEJ pathwayDNA proteinProcessing enzymesDefective repairCellular sensitivityCell deathStrand breaksPolymerase betaSubunit inhibitorPolymeraseSmall deletionsMechanistic insightsNHEJLocal 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 penetrationTreatmentRadiosensitizerChemotherapy2-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 analoguesDrugsGemcitabineCharacterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay
Surovtseva YV, Jairam V, Salem AF, Sundaram RK, Bindra RS, Herzon SB. Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay. Journal Of The American Chemical Society 2016, 138: 3844-3855. PMID: 26927829, PMCID: PMC5530877, DOI: 10.1021/jacs.6b00162.Peer-Reviewed Original ResearchConceptsRing finger protein 8DNA double-strand break repairDouble-strand break repairSmall molecule inhibitorsDSB repairBreak repairDNA damage checkpoint protein 1DNA damage response networkNatural productsSmall moleculesP53-binding protein 1Sites of DSBsFinger protein 8Protein 1Glycoside natural productsDNA repair pathwaysNew small molecule inhibitorsClass of compoundsBinding protein 1Small molecule DNALarge compound librariesPotent inhibitorRepair pathwaysCardiac glycosidesSecondary assays
2015
Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors
Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M, Kluger HM, Glickman JF, Powell SN, Bindra RS. Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors. Molecular Cancer Therapeutics 2015, 14: 326-342. PMID: 25512618, PMCID: PMC4326563, DOI: 10.1158/1535-7163.mct-14-0765.Peer-Reviewed Original ResearchConceptsDSB repair inhibitorsDouble-strand breaksDSB repairHomologous recombinationRepair inhibitorsCell-based small molecule screenSuccessful DSB repairDNA-damaging agentsPlate-based formatCell-based screenSmall-molecule screenGenomic integrityTumor cell survivalMammalian cellsHR repairDNA repairMolecule screenReporter systemSecondary assaysCell survivalDNA damageCancer cell linesTumor cellsNovel hitsMost cancer therapies
2013
Radiation sensitivity and sensitization in melanoma
Shahbazian D, Bindra RS, Kluger HM, Glazer PM. Radiation sensitivity and sensitization in melanoma. Pigment Cell & Melanoma Research 2013, 26: 928-930. PMID: 23870422, PMCID: PMC3866027, DOI: 10.1111/pcmr.12147.Peer-Reviewed Original Research
2010
Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130
Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 2201-2206. PMID: 20133863, PMCID: PMC2836641, DOI: 10.1073/pnas.0904783107.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorColonic NeoplasmsCrk-Associated Substrate ProteinDNA RepairDown-RegulationE2F4 Transcription FactorEnzyme InhibitorsGenes, BRCA1HumansPhenanthrenesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPromoter Regions, GeneticRad51 RecombinaseRadiation-Sensitizing AgentsRNA, Small InterferingConceptsHomology-dependent repairBase excision repair factorsExcision repair factorsPARP inhibitionRole of PARPPARP inhibitorsRepair factorsExpression of BRCA1DNA repairDNA breaksHypoxic cancer cellsRAD51SiRNA knockdownDNA damagePARP-1P130 expressionCancer therapyP130Cancer cellsPARPRad51 promoterHPV E7BRCA1E7 expressionSiRNAs
2007
Co-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network
Bindra RS, Glazer PM. Co-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network. Cancer Letters 2007, 252: 93-103. PMID: 17275176, DOI: 10.1016/j.canlet.2006.12.011.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCell Cycle ProteinsCell HypoxiaCell Line, TumorDNA Mismatch RepairDown-RegulationGene Expression Regulation, NeoplasticGenomic InstabilityHumansHypoxia-Inducible Factor 1MutL Protein Homolog 1MutS Homolog 2 ProteinNeoplasmsNuclear ProteinsPromoter Regions, GeneticProto-Oncogene Proteins c-mycRepressor ProteinsConceptsHypoxia-inducible factorHypoxia-induced genetic instabilityGene expressionGenetic instabilityRepair genesStress response pathwaysC-Myc/MaxStress response factorsMismatch repair genesCancer cellsRepair gene expressionMax complexesCoordinated repressionKey genesDNA repairMMR pathwayProximal promoterMicroenvironmental stressMax networkMMR gene expressionDeficient cellsGenesRepressionEssential roleMMR genes
2006
Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia
Bindra RS, Glazer PM. Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene 2006, 26: 2048-2057. PMID: 17001309, DOI: 10.1038/sj.onc.1210001.Peer-Reviewed Original ResearchConceptsDNA repair pathwaysE2F siteRepair pathwaysHypoxia-induced genetic instabilityGenetic instabilityCoordinated transcriptional programRepair genesHypoxic stressRecombinational repair genesDownregulation of Rad51RAD51 gene expressionTranscriptional programsProximal promoterGene expressionNuclear accumulationMechanistic basisDNA mismatch repair genesRAD51BRCA1 promoterGenesPromoterMismatch repair genesBRCA1 geneNew therapeutic strategiesSimilar mechanism
2005
Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner
Gibson SL, Bindra RS, Glazer PM. Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner. Cancer Research 2005, 65: 10734-10741. PMID: 16322218, DOI: 10.1158/0008-5472.can-05-1160.Peer-Reviewed Original ResearchConceptsDNA repairAtaxia telangiectasiaSerine/threonine kinaseDNA damageRelated kinase ATMKinase ataxia telangiectasiaNBS1-dependent mannerDNA repair factorsPhosphorylation of Chk2Hypoxic growth conditionsKinase ATMThreonine kinaseChk2 activationReplication forksRepair factorsChk2Apoptotic pathwayCell survivalNovel pathwayCycle arrestPhosphorylationGrowth conditionsDependent mannerPathwayCellsAlterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability
BINDRA RS, SCHAFFER PJ, MENG A, WOO J, MÅSEIDE K, ROTH ME, LIZARDI P, HEDLEY DW, BRISTOW RG, GLAZER PM. Alterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability. Annals Of The New York Academy Of Sciences 2005, 1059: 184-195. PMID: 16382054, DOI: 10.1196/annals.1339.049.Peer-Reviewed Original ResearchConceptsGenetic instabilityHomologous recombinationRAD51 expressionDNA repair gene expressionSuch genetic instabilityPost-hypoxic cellsDNA repair genesRepair gene expressionNumerous cell linesExpression of RAD51HR pathwayHR repairHypoxia-inducible factorGene expressionCell cycleRepair genesNovel mechanismHypoxic stressIndependent mannerPost-hypoxic periodCell linesCancer cellsCritical mediatorGenesExpressionHypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells
Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, Bristow RG. Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiotherapy And Oncology 2005, 76: 168-176. PMID: 16026872, DOI: 10.1016/j.radonc.2005.06.025.Peer-Reviewed Original ResearchConceptsProstate cancer cellsCell cycle distributionCancer cellsP53 genotypeCycle distributionProtein expressionRNA expressionPoor clinical outcomeInduction of hypoxiaMalignant prostate cell linesAbility of hypoxiaRepair genesProstate cell linesHypoxia-induced apoptosisHR-associated genesDouble-strand break repair genesClinical outcomesDNA double-strand break repair genesProstate cancerGene expressionIntratumoral hypoxiaVEGF expressionBPH-1Tumor cellsObserved genetic instability