2024
Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition
Rackear M, Quijano E, Ianniello Z, Colón-Ríos D, Krysztofiak A, Abdullah R, Liu Y, Rogers F, Ludwig D, Dwivedi R, Bleichert F, Glazer P. Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition. Oncotarget 2024, 15: 699-713. PMID: 39352803, PMCID: PMC11444335, DOI: 10.18632/oncotarget.28651.Peer-Reviewed Original ResearchConceptsTumor targetingMonoclonal antibody therapyTumor-specific targetingCell uptakeNucleic acid bindingCell surface antigensAntibody therapyHuman variantsClinical successCell-penetrating antibodiesAcid bindingSystemic administrationSurface antigensTumorRAD51 inhibitionAntibody platformMechanism of cell penetrationBind RAD51AntibodiesFull-lengthSpecific targetsCell penetrationDisease targetsCellsAutoantibodies
2022
LINE-1 activation in the cerebellum drives ataxia
Takahashi T, Stoiljkovic M, Song E, Gao XB, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu ZW, Kristant A, Zhang Y, Sulkowski P, Glazer PM, Kaczmarek LK, Horvath TL, Iwasaki A. LINE-1 activation in the cerebellum drives ataxia. Neuron 2022, 110: 3278-3287.e8. PMID: 36070749, PMCID: PMC9588660, DOI: 10.1016/j.neuron.2022.08.011.Peer-Reviewed Original ResearchConceptsLINE-1 activationL1 activationAtaxia telangiectasia patientsNuclear element-1Transposable elementsEpigenetic silencersHuman genomeL1 promoterMolecular regulatorsDNA damagePurkinje cell dysfunctionElement 1First direct evidenceTelangiectasia patientsDirect targetingCerebellar expressionNeurodegenerative diseasesDisease etiologyCalcium homeostasis
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 deathPARPiBBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer
Raimundo L, Paterna A, Calheiros J, Ribeiro J, Cardoso DSP, Piga I, Neto SJ, Hegan D, Glazer PM, Indraccolo S, Mulhovo S, Costa JL, Ferreira M, Saraiva L. BBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer. British Journal Of Pharmacology 2021, 178: 3627-3647. PMID: 33899955, PMCID: PMC9124438, DOI: 10.1111/bph.15506.Peer-Reviewed Original ResearchConceptsTriple-negative breastOvarian cancerXenograft mouse modelMouse modelAntitumour activityAdvanced ovarian cancerCancer cellsPatient-derived cell linesHomologous DNA repairOvarian cancer cellsNon-malignant cellsPatient-derived cellsMarked synergistic effectAvailable therapiesCombination therapyCell cycle arrestReactive oxygen species generationSide effectsDNA repair-related genesSingle agentTherapeutic outcomesCancerOxygen species generationPersonalized treatmentResistant cancersNanoparticles for delivery of agents to fetal lungs
Ullrich SJ, Freedman-Weiss M, Ahle S, Mandl HK, Piotrowski-Daspit AS, Roberts K, Yung N, Maassel N, Bauer-Pisani T, Ricciardi AS, Egan ME, Glazer PM, Saltzman WM, Stitelman DH. Nanoparticles for delivery of agents to fetal lungs. Acta Biomaterialia 2021, 123: 346-353. PMID: 33484911, PMCID: PMC7962939, DOI: 10.1016/j.actbio.2021.01.024.Peer-Reviewed Original ResearchConceptsFetal lungCellular uptakeIntra-amniotic routeRoute of deliveryCongenital lung diseaseDelivery of agentsIntra-amniotic deliveryRelative cellular uptakeNanoparticlesFetal treatmentDiaphragmatic herniaLung diseaseFetal therapyLung tissueFetal miceIntravenous deliveryCystic fibrosisLungLung therapyInterventional technologiesTherapeutic agentsEndothelial cellsCell populationsEffective targetingTherapy
2020
Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway
Lu Y, Liu Y, Oeck S, Zhang GJ, Schramm A, Glazer PM. Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway. Cancer Research 2020, 80: 4655-4667. PMID: 32873635, PMCID: PMC7642024, DOI: 10.1158/0008-5472.can-20-1192.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAniline CompoundsAnimalsAntineoplastic AgentsCarcinoma, Non-Small-Cell LungCell HypoxiaCell Line, TumorDrug Resistance, NeoplasmHumansLung NeoplasmsMAP Kinase Signaling SystemMiceProtein Kinase InhibitorsReceptor, Fibroblast Growth Factor, Type 1Up-RegulationXenograft Model Antitumor AssaysConceptsEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitorsEpithelial-mesenchymal transitionNon-small cell lung cancer (NSCLC) cell line H1975Fibroblast growth factor receptor 1 expressionMEK inhibitorsNSCLC cell line H1975EGFR-TKI resistanceEGFR-TKI osimertinibOverexpression of FGFR1Receptor 1 expressionEGFR-TKI sensitivityExpression of FGFR1Lung cancer cellsAttractive therapeutic strategyMAPK pathwayProapoptotic factor BimClinical efficacyConventional therapyDevelopment of resistanceEGFR mutationsSelective small molecule inhibitorsTKI resistanceKnockdown of FGFR1Therapeutic strategiesKu80-Targeted pH-Sensitive Peptide–PNA Conjugates Are Tumor Selective and Sensitize Cancer Cells to Ionizing Radiation
Kaplan AR, Pham H, Liu Y, Oyaghire S, Bahal R, Engelman DM, Glazer PM. Ku80-Targeted pH-Sensitive Peptide–PNA Conjugates Are Tumor Selective and Sensitize Cancer Cells to Ionizing Radiation. Molecular Cancer Research 2020, 18: 873-882. PMID: 32098827, PMCID: PMC7272299, DOI: 10.1158/1541-7786.mcr-19-0661.Peer-Reviewed Original ResearchConceptsCancer cellsTumor cellsLocal tumor irradiationTumor-selective radiosensitizationMouse tumor modelsKu80 expressionNovel agentsTumor irradiationTumor growthTumor microenvironmentTumor modelRadiation treatmentTherapeutic agentsSubcutaneous mouse tumor modelTumorsMiceCancer therapyHealthy tissueAcute toxicitySpecific targetingSelective effectPNA antisenseTumor-SelectiveAcidic culture conditionsSensitize cancer cells
2019
Mitochondrial DNA stress signalling protects the nuclear genome
Wu Z, Oeck S, West AP, Mangalhara KC, Sainz AG, Newman LE, Zhang XO, Wu L, Yan Q, Bosenberg M, Liu Y, Sulkowski PL, Tripple V, Kaech SM, Glazer PM, Shadel GS. Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism 2019, 1: 1209-1218. PMID: 32395698, PMCID: PMC7213273, DOI: 10.1038/s42255-019-0150-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell NucleusCytosolDNA DamageDNA-Binding ProteinsDNA, MitochondrialGenomeHigh Mobility Group ProteinsInterferon-Stimulated Gene Factor 3InterferonsMembrane ProteinsMiceMice, KnockoutMice, NudeNF-kappa BNucleotidyltransferasesProtein Serine-Threonine KinasesSignal TransductionConceptsMtDNA stressNuclear DNAGene expressionThousands of copiesMost cell typesRepair responseAcute antiviral responseNuclear genomeCircular mtDNAHigher-order structureInterferon gene expressionEssential proteinsMitochondrial DNACultured primary fibroblastsDNA stressUnphosphorylated formInterferon-stimulated gene expressionMouse melanoma cellsNDNA repairSignaling responseOxidative phosphorylationNDNA damageMtDNA damageMtDNAPrimary fibroblasts
2018
In utero nanoparticle delivery for site-specific genome editing
Ricciardi AS, Bahal R, Farrelly JS, Quijano E, Bianchi AH, Luks VL, Putman R, López-Giráldez F, Coşkun S, Song E, Liu Y, Hsieh WC, Ly DH, Stitelman DH, Glazer PM, Saltzman WM. In utero nanoparticle delivery for site-specific genome editing. Nature Communications 2018, 9: 2481. PMID: 29946143, PMCID: PMC6018676, DOI: 10.1038/s41467-018-04894-2.Peer-Reviewed Original ResearchConceptsSite-specific genome editingReversal of splenomegalyPeptide nucleic acidIntra-amniotic administrationBlood hemoglobin levelsMonogenic disordersNanoparticle deliveryPolymeric nanoparticlesPostnatal elevationGestational ageHemoglobin levelsImproved survivalPediatric morbidityDisease improvementHuman β-thalassemiaReticulocyte countNormal organ developmentMouse modelNormal rangeEarly interventionGenome editingOff-target mutationsPostnatal growthGene editingVersatile method
2016
In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery
Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, Lu YC, Bhunia DC, Manna A, Greiner DL, Brehm MA, Cheng CJ, López-Giráldez F, Ricciardi A, Beloor J, Krause DS, Kumar P, Gallagher PG, Braddock DT, Mark Saltzman W, Ly DH, Glazer PM. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nature Communications 2016, 7: 13304. PMID: 27782131, PMCID: PMC5095181, DOI: 10.1038/ncomms13304.Peer-Reviewed Original ResearchConceptsNanoparticle deliveryGene correctionReversal of splenomegalyPeptide nucleic acidLow off-target effectsVivo correctionGenome editingOff-target effectsGene editingHaematopoietic stem cellsNucleic acidsDonor DNAStem cellsΓPNAΒ-thalassaemiaNanoparticlesDeliveryEditingSCF treatmentTriplex formation
2014
MicroRNA silencing for cancer therapy targeted to the tumour microenvironment
Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, Saltzman WM, Slack FJ. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 2014, 518: 107-110. PMID: 25409146, PMCID: PMC4367962, DOI: 10.1038/nature13905.Peer-Reviewed Original Research
2001
Chromosome Targeting at Short Polypurine Sites by Cationic Triplex-forming Oligonucleotides*
Vasquez K, Dagle J, Weeks D, Glazer P. Chromosome Targeting at Short Polypurine Sites by Cationic Triplex-forming Oligonucleotides*. Journal Of Biological Chemistry 2001, 276: 38536-38541. PMID: 11504712, DOI: 10.1074/jbc.m101797200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceCationsChromosomesCOS CellsDiaminesDNADNA Mutational AnalysisDose-Response Relationship, DrugEthylenediaminesFicusinGenes, ReporterGenes, SuppressorGenetic TechniquesGenomeIndicators and ReagentsMagnesiumMiceMice, KnockoutModels, GeneticMolecular Sequence DataMutagenesisMutagenesis, Site-DirectedNucleic Acid ConformationPotassiumProtein BindingPurinesRNA, TransferSequence Homology, Nucleic AcidConceptsChromosomal reporter geneMonkey COS cellsTarget siteSite-specific mutationsTriplex target sitesChromosome targetingEpisomal targetChromosomal targetsGene mutagenesisMammalian cellsSite-specific inductionChromosomal lociReporter geneCOS cellsGene knockoutGenomic DNAMouse cellsSite-directed modificationOligonucleotide bindsPhosphodiester bondShort sitesThird strand bindingPhosphodiester backboneSystemic administrationDNADirected gene modification via triple helix formation.
Gorman L, Glazer P. Directed gene modification via triple helix formation. 2001, 1: 391-9. PMID: 11899085, DOI: 10.2174/1566524013363771.Peer-Reviewed Original ResearchConceptsGene modificationNon-functional gene productMammalian genesGene productsGenomic DNASingle nucleotideDefective geneTriple helix formationGenetic diseasesTriplex formingGenesHelix formationEfficient targetingNucleic acidsDNAInitial stepGene therapyCorrect sequenceNucleotidesMutationsMoleculesImportant advancesSequenceTargetingModificationHypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice.
Xu X, Narayanan L, Dunklee B, Liskay R, Glazer P. Hypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice. Cancer Research 2001, 61: 3775-80. PMID: 11325851.Peer-Reviewed Original ResearchConceptsMismatch repairSimple sequence repeatsWild-type transgenic miceCell linesLambda cII geneMutation frequencyDNA mismatch repairHigher clonogenic survivalMMR-deficient miceLambda shuttle vectorTolerance phenotypeSequence repeatsPatterns of IRReporter geneRepeat sequencesMononucleotide repeat sequencesShuttle vectorSingle bp deletionCII geneNullizygous animalsNullizygous miceHypermutabilityBp deletionWild-type miceClonogenic survival
2000
Specific Mutations Induced by Triplex-Forming Oligonucleotides in Mice
Vasquez K, Narayanan L, Glazer P. Specific Mutations Induced by Triplex-Forming Oligonucleotides in Mice. Science 2000, 290: 530-533. PMID: 11039937, DOI: 10.1126/science.290.5491.530.Peer-Reviewed Original ResearchConceptsSomatic cellsSpecific genomic sitesEmbryonic stem cell technologyDuplex DNA sequencesGene functionGreater mutation frequenciesGenomic sitesGenome modificationChromosomal copyDNA sequencesSequence-controlled oligomersReporter geneStem cell technologyControl genesGerm-line mutationsGenesSpecific mutationsSupF geneControl oligomersMutationsMutation frequencyTransgenic miceOligonucleotideCellsMutation detectionIonizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways.
Zeng M, Narayanan L, Xu X, Prolla T, Liskay R, Glazer P. Ionizing radiation-induced apoptosis via separate Pms2- and p53-dependent pathways. Cancer Research 2000, 60: 4889-93. PMID: 10987303.Peer-Reviewed Original ResearchHigh-frequency intrachromosomal gene conversion induced by triplex-forming oligonucleotides microinjected into mouse cells
Luo Z, Macris M, Faruqi A, Glazer P. High-frequency intrachromosomal gene conversion induced by triplex-forming oligonucleotides microinjected into mouse cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 9003-9008. PMID: 10900269, PMCID: PMC16811, DOI: 10.1073/pnas.160004997.Peer-Reviewed Original ResearchConceptsTriple helix-forming oligonucleotidesLtk- cell lineTK geneChromosomal lociIntrachromosomal gene conversionMouse Ltk- cell lineSingle chromosomal locusFunctional tk geneGene conversion eventsSite-specific recombinationSequence-specific mannerCell linesSimplex virus thymidine kinase geneVirus thymidine kinase geneHerpes simplex virus thymidine kinase geneThymidine kinase geneGene conversionIdentical base compositionMammalian cellsDownstream genesConversion eventsChromosomal sitesBase compositionKinase geneMutant copiesMutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts
Andrew S, Xu X, Baross-Francis A, Narayanan L, Milhausen K, Liskay R, Jirik F, Glazer P. Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. Carcinogenesis 2000, 21: 1291-1296. PMID: 10874005, DOI: 10.1093/carcin/21.7.1291.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnimalsBase Pair MismatchCrosses, GeneticDNA RepairDNA Repair EnzymesDNA-Binding ProteinsFemaleFrameshift MutationGenes, ReporterGenotypeGerm-Line MutationMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, TransgenicMismatch Repair Endonuclease PMS2MutagenesisMutS Homolog 2 ProteinPoint MutationProteinsProto-Oncogene ProteinsConceptsPms2-deficient miceMsh2-deficient miceHereditary non-polyposis colorectal cancer patientsCII target geneDNA mismatch repair deficiencyColorectal cancer patientsPMS2 germline mutationsMismatch repair deficiencyReporter transgenic miceMutation frequencyLacI target geneCancer patientsTarget genesMouse modelKnockout miceTumor spectrumTransgenic miceFrameshift mutationGermline mutationsMiceRepair deficiencyPMS2 deficiencySupF target geneMSH2Predominant mutations
1999
The Tyr-265-to-Cys mutator mutant of DNA polymerase β induces a mutator phenotype in mouse LN12 cells
Clairmont C, Narayanan L, Sun K, Glazer P, Sweasy J. The Tyr-265-to-Cys mutator mutant of DNA polymerase β induces a mutator phenotype in mouse LN12 cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 9580-9585. PMID: 10449735, PMCID: PMC22251, DOI: 10.1073/pnas.96.17.9580.Peer-Reviewed Original ResearchConceptsMutator mutantsDNA polymerase betaTyr-265Mutator phenotypePolymerase betaWild-type DNA polymerase betaWild-type DNA polymeraseWild-type proteinBase excision repairRat DNA polymerase betaSpontaneous mutation frequencyDNA polymerase βDNA polymerase IMammalian cellsMutator polymeraseComplementation systemBeta mutantsExcision repairPolymerase IMutantsMutator activityGenetic instabilityHuman cellsPolymerase βEscherichia coliDifferent mutator phenotypes in Mlh1- versus Pms2-deficient mice
Yao X, Buermeyer A, Narayanan L, Tran D, Baker S, Prolla T, Glazer P, Liskay R, Arnheim N. Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 6850-6855. PMID: 10359802, PMCID: PMC22005, DOI: 10.1073/pnas.96.12.6850.Peer-Reviewed Original ResearchConceptsMismatch repairMutator phenotypeMutation rateDifferent chromosomal locationsSingle-molecule PCRDinucleotide repeat lociMutation frequencyDNA mismatch repairMononucleotide repeat tractsChromosomal locationCellular processesDNA repair capacityHigh mutation frequencyDifferent mutator phenotypesMultiple genetic alterationsKnockout strainRepeat tractMlh1pMLH1 MMR geneRepeat lociGenetic alterationsDifferent tumor spectrumRepair capacityTumor developmentMMR genes