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
2023
Response to: Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect
Takahashi T, Stoiljkovic M, Song E, Gao X, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu Z, Kristant A, Zhang Y, Sulkowski P, Glazer P, Kaczmarek L, Horvath T, Iwasaki A. Response to: Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect. Neuron 2023, 111: 612-613. PMID: 36863323, DOI: 10.1016/j.neuron.2023.02.006.Peer-Reviewed Original Research
2022
Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984
Kim JW, McKay RR, Radke MR, Zhao S, Taplin ME, Davis NB, Monk P, Appleman LJ, Lara PN, Vaishampayan UN, Zhang J, Paul AK, Bubley G, Van Allen EM, Unlu S, Huang Y, Loda M, Shapiro GI, Glazer PM, LoRusso PM, Ivy SP, Shyr Y, Swisher EM, Petrylak DP. Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984. Journal Of Clinical Oncology 2022, 41: 871-880. PMID: 36256912, PMCID: PMC9901975, DOI: 10.1200/jco.21.02947.Peer-Reviewed Original ResearchConceptsMetastatic castration-resistant prostate cancerRadiographic progression-free survivalMedian radiographic progression-free survivalCastration-resistant prostate cancerArm AProstate cancerAdverse eventsGrade 3Progressive metastatic castration-resistant prostate cancerEndothelial growth factor receptor inhibitorEnd pointHomologous recombination repair genesGrowth factor receptor inhibitorsPrimary end pointSecondary end pointsProgression-free survivalRecombination repair genesPoly (ADP-ribose) polymerase inhibitionTreat setTreat patientsClinical outcomesRandomized trialsPreclinical modelsReceptor inhibitorsCediranibMetastatic and multiply relapsed SDH‐deficient GIST and paraganglioma displays clinical response to combined poly ADP‐ribose polymerase inhibition and temozolomide
Singh C, Bindra RS, Glazer PM, Vasquez JC, Pashankar F. Metastatic and multiply relapsed SDH‐deficient GIST and paraganglioma displays clinical response to combined poly ADP‐ribose polymerase inhibition and temozolomide. Pediatric Blood & Cancer 2022, 70: e30020. PMID: 36151992, DOI: 10.1002/pbc.30020.Peer-Reviewed Original ResearchLINE-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 homeostasisAn ELISA-based platform for rapid identification of structure-dependent nucleic acid–protein interactions detects novel DNA triplex interactors
Economos NG, Thapar U, Balasubramanian N, Karras GI, Glazer PM. An ELISA-based platform for rapid identification of structure-dependent nucleic acid–protein interactions detects novel DNA triplex interactors. Journal Of Biological Chemistry 2022, 298: 102398. PMID: 35988651, PMCID: PMC9493393, DOI: 10.1016/j.jbc.2022.102398.Peer-Reviewed Original ResearchConceptsNucleic acid structuresNucleic acid-protein interactionsNucleotide excision repairSingle-strand annealing repairDouble-strand break intermediatesUnusual nucleic acid structuresNovel interactorNucleic acid interactionsHigh-throughput platformCellular processesFactor localizationAcid structureExcision repairRelevant lociHuman cellsGene editingAcid interactionsInteractorsTherapeutic gene editingNucleic acidsDNA triplexesRapid identificationComparative approachGenomeTriplexes
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 deathPARPiRegulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery
Hayman TJ, Glazer PM. Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery. International Journal Of Molecular Sciences 2021, 22: 12761. PMID: 34884568, PMCID: PMC8657976, DOI: 10.3390/ijms222312761.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksInnate immune machineryGenomic integrityDNA-damaging therapiesDNA damage response systemDNA DSB repair pathwaysImmune machineryCell-autonomous responsesDNA damage responseDSB repair pathwaysDouble-strand breaksDamage responseInnate immune pathwaysRepair pathwaysCell survivalDNA damageUnderappreciated roleProper repairImmune pathwaysMachineryPathwayAdaptive immune responsesSignificant normal tissue toxicityMost therapeutic studiesImmune responseBBIT20 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 cancersClinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation
Kim J, Cardin DB, Vaishampayan UN, Kato S, Grossman SR, Glazer P, Shyr Y, Ivy SP, LoRusso P. Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. The Oncologist 2021, 26: e1104-e1109. PMID: 33742489, PMCID: PMC8265343, DOI: 10.1002/onco.13758.Peer-Reviewed Original ResearchConceptsMetastatic pancreatic adenocarcinomaHomologous recombination DNA repair deficiencyMetastatic pancreatic ductal adenocarcinomaPancreatic ductal adenocarcinomaOlaparib combinationStable diseaseBRCA mutationsAdverse eventsDuctal adenocarcinomaCommon treatment-related adverse eventsVascular endothelial growth factor receptor inhibitorEndothelial growth factor receptor inhibitorTreatment-related adverse eventsGrowth factor receptor inhibitorsPrior systemic chemotherapyMedian overall survivalObjective response rateGermline BRCA mutationsBest overall responseExpression of BRCA1/2Restaging scanCancer cell linesPrimary endpointStudy drugSystemic chemotherapyThe NIH Somatic Cell Genome Editing program
Saha K, Sontheimer EJ, Brooks PJ, Dwinell MR, Gersbach CA, Liu DR, Murray SA, Tsai SQ, Wilson RC, Anderson DG, Asokan A, Banfield JF, Bankiewicz KS, Bao G, Bulte JWM, Bursac N, Campbell JM, Carlson DF, Chaikof EL, Chen ZY, Cheng RH, Clark KJ, Curiel DT, Dahlman JE, Deverman BE, Dickinson ME, Doudna JA, Ekker SC, Emborg ME, Feng G, Freedman BS, Gamm DM, Gao G, Ghiran IC, Glazer PM, Gong S, Heaney JD, Hennebold JD, Hinson JT, Khvorova A, Kiani S, Lagor WR, Lam KS, Leong KW, Levine JE, Lewis JA, Lutz CM, Ly DH, Maragh S, McCray PB, McDevitt TC, Mirochnitchenko O, Morizane R, Murthy N, Prather RS, Ronald JA, Roy S, Roy S, Sabbisetti V, Saltzman WM, Santangelo PJ, Segal DJ, Shimoyama M, Skala MC, Tarantal AF, Tilton JC, Truskey GA, Vandsburger M, Watts JK, Wells KD, Wolfe SA, Xu Q, Xue W, Yi G, Zhou J. The NIH Somatic Cell Genome Editing program. Nature 2021, 592: 195-204. PMID: 33828315, PMCID: PMC8026397, DOI: 10.1038/s41586-021-03191-1.Peer-Reviewed Original ResearchConceptsDownstream functional consequencesGenome modificationHuman genomeGenome editingGenome editorsSomatic cellsHuman cellsFunctional consequencesBiomedical research communityGenomeLarge animalsBiological systemsCellsHuman healthHuman biological systemsEditingVivoAnimal modelsNew therapiesNew opportunitiesWide rangeConsortiumCooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance
Dong YL, Vadla GP, Lu J, Ahmad V, Klein TJ, Liu LF, Glazer PM, Xu T, Chabu CY. Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance. Communications Biology 2021, 4: 374. PMID: 33742110, PMCID: PMC7979758, DOI: 10.1038/s42003-021-01898-5.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsAnimalsAnimals, Genetically ModifiedCell ProliferationCytokinesDrosophila melanogasterDrosophila ProteinsFemaleGene Expression Regulation, NeoplasticGenes, rasHumansJanus KinasesLung NeoplasmsMaleMice, NudeMice, TransgenicParacrine CommunicationRadiation ToleranceSignal TransductionSTAT Transcription FactorsTumor BurdenTumor Suppressor Protein p53Xenograft Model Antitumor AssaysConceptsTumor microenvironmentTumor radioresistanceRas clonesOncogenic Ras mutationsClinical outcomesRA tissuesCancer patientsJAK/STATRadiation therapyRobust tumorOncogenic RasTherapy outcomeTumor resistanceTumor tissueRas mutationsTumor cellsJAK/OutcomesRadioresistanceCellular responsesTissueCell-cell interactionsPatientsCytokinesRadiotherapyTargeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides
Dharmaratne NU, Kaplan AR, Glazer PM. Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides. Cells 2021, 10: 541. PMID: 33806273, PMCID: PMC8000199, DOI: 10.3390/cells10030541.Peer-Reviewed Original ResearchConceptsNucleic acid analoguesPH-sensitive peptideLow insertion peptideAcidic tumor microenvironmentPoor bioavailabilityInsertion peptideFluorescent dyeHigh toxicitySelective deliveryAcid analoguesSmall molecule inhibitorsNanoparticlesCancer therapeuticsMolecule inhibitorsDyePeptidesReview articleAcidityPHLIPPromising toolBioavailabilityAnaloguesDeliveryHypoxic tumor microenvironmentClinical 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
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 strategiesOncometabolites 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 executionMutationsKu80-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
Impact of hypoxia on DNA repair and genome integrity
Kaplan AR, Glazer PM. Impact of hypoxia on DNA repair and genome integrity. Mutagenesis 2019, 35: 61-68. PMID: 31282537, PMCID: PMC7317153, DOI: 10.1093/mutage/gez019.Peer-Reviewed Original ResearchConceptsDNA repairDNA repair pathwaysHomology-directed repairBase excision repairGenome integrityRepair pathwaysGenomic instabilityExcision repairHypoxia mimeticMismatch repairDiverse mechanismsImpact of hypoxiaCancer progressionMutation frequencyTumor biologyTumor microenvironmentDevelopment of metastasesPotential clinical relevanceProfound effectRepairBiologyHypoxiaPathwayHallmarkMicroenvironmentCediranib 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