2021
Cooperation 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 interactionsPatientsCytokinesRadiotherapy
2020
Ku80-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
Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform.
Bindra R, Sundaram R, Aiello R, Marshall D, Bourassa P, Csengery J, Zhang Q, Robinson B, lopresti-Morrow L, Bechtold J, Tylaska L, Paradis T, Paralkar V, Hellsund P, Glazer P. Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform. Journal Of Clinical Oncology 2019, 37: e14664-e14664. DOI: 10.1200/jco.2019.37.15_suppl.e14664.Peer-Reviewed Original ResearchHomologous recombination deficiencyHRD statusAnti-cancer agentsClinical trialsSignificant bone marrow toxicityTumor cellsInhibitor efficacyPhase I clinical trialIND-enabling studiesDose-limiting toxicityBone marrow toxicitySignificant tumor cell killingSmall molecule anti-cancer agentNormal tissue toxicityTumor cell killingTumor-targeting approachesPARP inhibitor efficacyRelevant chemotherapyVivo tumor modelsMarrow toxicityBRCA1/2 mutationsComplete sparingBone marrowSolid tumorsChemotherapy
2018
Krebs-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
Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors.
Bindra R, Sulkowski P, Corso C, Glazer P, Shuch B. Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors. Journal Of Clinical Oncology 2017, 35: 11586-11586. DOI: 10.1200/jco.2017.35.15_suppl.11586.Peer-Reviewed Original ResearchAcute myeloid leukemiaMulti-center phase II trialIDH1/2 mutationsPARP inhibitorsMutant IDH1/2 inhibitorsPhase II trialEfficacy of olaparibPoly (ADP-ribose) polymerase (PARP) inhibitorsRelated gene mutationsHomologous recombination defectsII trialIDH1/2 inhibitorsMyeloid leukemiaIsocitrate dehydrogenase 1Therapeutic strategiesPathologic processesSmall molecule inhibitorsIDH1/2-mutant tumorsSmall molecule inhibitionTumor progressionDNA repair inhibitorsPolymerase inhibitorsModern oncologyTumor cellsKey mediator2-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
1998
Mutagenesis induced by the tumor microenvironment
Yuan J, Glazer P. Mutagenesis induced by the tumor microenvironment. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 1998, 400: 439-446. PMID: 9685702, DOI: 10.1016/s0027-5107(98)00042-6.Peer-Reviewed Original Research