2021
BBIT20 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 chemotherapyCooperation 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 interactionsPatientsCytokinesRadiotherapyClinical 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 inhibitionTumorsOlaparibNanoparticles 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
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
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
2017
2-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
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
2000
Mutagenesis 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 mutationsCyclin D1 expression and early breast cancer recurrence following lumpectomy and radiation
Turner B, Gumbs A, Carter D, Glazer P, Haffty B. Cyclin D1 expression and early breast cancer recurrence following lumpectomy and radiation. International Journal Of Radiation Oncology • Biology • Physics 2000, 47: 1169-1176. PMID: 10889369, DOI: 10.1016/s0360-3016(00)00525-3.Peer-Reviewed Original ResearchConceptsIpsilateral breast tumor recurrenceBreast cancer patientsDistant disease-free survivalCancer patientsRadiation therapyOverall survivalEarly-stage breast cancer patientsEarly breast cancer recurrenceAxillary lymph node involvementCycD1 expressionTotal median doseBreast tumor recurrenceDisease-free survivalLymph node involvementBreast cancer populationBreast cancer recurrenceBreast tumor relapseCyclin D1 expressionCyclin D1 levelsMedian doseNode involvementMetastatic diseaseLate relapsePrognostic significancePatient populationMutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy
Turner B, Gumbs A, Carbone C, Carter D, Glazer P, Haffty B. Mutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy. Cancer 2000, 88: 1091-1098. PMID: 10699900, DOI: 10.1002/(sici)1097-0142(20000301)88:5<1091::aid-cncr21>3.0.co;2-y.Peer-Reviewed Original ResearchConceptsIpsilateral breast tumor recurrenceMutant p53 protein overexpressionBreast carcinoma patientsP53 protein overexpressionBreast tumor recurrenceDistant disease-free survivalDisease-free survivalCase-control studyPrimary breast tumorsCarcinoma patientsMutant p53 proteinBreast tumor relapseRadiation therapyTumor recurrenceBreast tumorsFree survivalProtein overexpressionPrognostic significanceP53 proteinEstrogen receptorTumor relapseIndex caseP53 mutationsControl casesP53 protein immunoreactivityPrognostic significance of cyclin D1 protein levels in early‐stage larynx cancer treated with primary radiation
Yoo S, Carter D, Turner B, Sasaki C, Son Y, Wilson L, Glazer P, Haffty B. Prognostic significance of cyclin D1 protein levels in early‐stage larynx cancer treated with primary radiation. International Journal Of Cancer 2000, 90: 22-28. PMID: 10725854, DOI: 10.1002/(sici)1097-0215(20000220)90:1<22::aid-ijc3>3.0.co;2-t.Peer-Reviewed Original ResearchConceptsEarly-stage larynx cancerLocal relapsePrognostic significanceLarynx cancerTotal median dosePrimary radiation therapySquamous cell carcinomaCell nuclear antigen levelsParaffin-embedded specimensSignificant clinical implicationsCase-control designPercent distributionLarynx cancer patientsCyclin D1 protein levelsCyclin D1 levelsMedian doseControl patientsLocal recurrenceAntigen levelsCancer patientsCell carcinomaDaily fractionsRadiation therapyIndex caseClinical information
1999
BRCA1/BRCA2 in breast-conserving therapy.
Turner B, Glazer P, Haffty B. BRCA1/BRCA2 in breast-conserving therapy. Journal Of Clinical Oncology 1999, 17: 3689. PMID: 10550169.Peer-Reviewed Original ResearchBRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.
Turner B, Harrold E, Matloff E, Smith T, Gumbs A, Beinfield M, Ward B, Skolnick M, Glazer P, Thomas A, Haffty B. BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. Journal Of Clinical Oncology 1999, 17: 3017-24. PMID: 10506595, DOI: 10.1200/jco.1999.17.10.3017.Peer-Reviewed Original ResearchConceptsBreast cancer patientsDeleterious BRCA1/2 mutationsCancer patientsBRCA1/2 mutationsControl patientsAge 40BRCA2 mutationsRadiation therapyControl breast cancer patientsNew primary breast cancerRecurrent breast cancer patientsEarly-onset breast cancer patientsBRCA1/BRCA2 mutationsBreast-conserving managementBreast-conserving therapySecond primary tumorsPrimary breast cancerOutcome of treatmentBRCA2 germline mutationsBRCA1/BRCA2 germline mutationsSalvage mastectomySystemic progressionLocal relapseMedian timeRecurrent cancer
1998
Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways.
Turner B, Zhang J, Gumbs A, Maher M, Kaplan L, Carter D, Glazer P, Hurst H, Haffty B, Williams T. Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. Cancer Research 1998, 58: 5466-72. PMID: 9850080.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesBreastBreast NeoplasmsDNA-Binding ProteinsEpitheliumFemaleHumansImmunohistochemistryPrognosisPromoter Regions, GeneticReceptor, ErbB-2Receptor, IGF Type 1Receptors, EstrogenReceptors, Growth FactorReceptors, ProgesteroneSignal TransductionTranscription Factor AP-2Transcription FactorsTumor Cells, CulturedUp-RegulationConceptsAP-2 transcription factorsAP-2-binding sitesTranscription factorsAP-2gammaAP-2alphaAP-2 gene familyAP-2 geneAP-2 family membersInsulin-like growth factor I receptorAP-2 familySignal transduction moleculesAP-2 proteinsAP-2alpha proteinMammalian developmentGene familyHuman breast cancerGrowth factor receptorTransduction moleculesProximal promoterBreast cancerReceptor promoterMultiple growth factorsBreast cancer cell linesCell growthAP-2gamma expression
1996
Other transgenic mutation assays: Tissue specificity of spontaneous point mutations in λsupF transgenic mice
Leach E, Narayanan L, Havre P, Gunther E, Yeasky T, Glazer P. Other transgenic mutation assays: Tissue specificity of spontaneous point mutations in λsupF transgenic mice. Environmental And Molecular Mutagenesis 1996, 28: 459-464. PMID: 8991078, DOI: 10.1002/(sici)1098-2280(1996)28:4<459::aid-em23>3.0.co;2-d.Peer-Reviewed Original Research