2019
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, Zhang J, Song C, Zarr M, Zhou X, Han X, Archer KA, O’Neill T, Herbst RS, Boto AN, Sanmamed MF, Langermann S, Rimm DL, Chen L. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nature Medicine 2019, 25: 656-666. PMID: 30833750, PMCID: PMC7175920, DOI: 10.1038/s41591-019-0374-x.Peer-Reviewed Original ResearchConceptsNormalization cancer immunotherapyTumor microenvironmentSiglec-15Antibody blockadeCancer immunotherapyImmune suppressorMyeloid cellsAntigen-specific T cell responsesB7-H1/PDTumor-infiltrating myeloid cellsB7-H1 moleculesAnti-tumor immunityT cell responsesPotential targetImmune evasion mechanismsInhibits tumor growthMacrophage colony-stimulating factorColony-stimulating factorB7-H1Evasion mechanismsMouse modelHuman cancer cellsTumor growthCell responsesGenetic ablation
2018
A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers
Gettinger SN, Choi J, Mani N, Sanmamed MF, Datar I, Sowell R, Du VY, Kaftan E, Goldberg S, Dong W, Zelterman D, Politi K, Kavathas P, Kaech S, Yu X, Zhao H, Schlessinger J, Lifton R, Rimm DL, Chen L, Herbst RS, Schalper KA. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nature Communications 2018, 9: 3196. PMID: 30097571, PMCID: PMC6086912, DOI: 10.1038/s41467-018-05032-8.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAntibodies, BlockingCarcinogenesisCarcinoma, Non-Small-Cell LungCell ProliferationCytotoxicity, ImmunologicHistocompatibility Antigens Class IHumansLung NeoplasmsLymphocyte ActivationLymphocytes, Tumor-InfiltratingMaleMice, Inbred NODMice, SCIDMutant ProteinsMutationPeptidesPhenotypeProgrammed Cell Death 1 ReceptorReproducibility of ResultsSurvival AnalysisTobaccoConceptsImmune checkpoint blockersCheckpoint blockersQuantitative immunofluorescenceNon-small cell lung carcinoma patientsCell lung carcinoma patientsNon-small cell lung carcinomaPatient-derived xenograft modelsIntratumoral T cellsMultiplexed quantitative immunofluorescencePD-1 blockadeLevels of CD3Lung carcinoma patientsCell lung carcinomaT cell proliferationPre-treatment samplesTIL phenotypeSurvival benefitCarcinoma patientsEffector capacityLung carcinomaT cellsWhole-exome DNA sequencingXenograft modelFavorable responseBlockers
2016
KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib
Nilsson MB, Giri U, Gudikote J, Tang X, Lu W, Tran H, Fan Y, Koo A, Diao L, Tong P, Wang J, Herbst R, Johnson BE, Ryan A, Webster A, Rowe P, Wistuba II, Heymach JV. KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib. Clinical Cancer Research 2016, 22: 1940-1950. PMID: 26578684, PMCID: PMC4834253, DOI: 10.1158/1078-0432.ccr-15-1994.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Non-Small-Cell LungCell Line, TumorCell MovementCell ProliferationHumansHypoxia-Inducible Factor 1, alpha SubunitLung NeoplasmsP38 Mitogen-Activated Protein KinasesPiperidinesProtein Kinase InhibitorsProto-Oncogene Proteins c-metQuinazolinesSignal TransductionTOR Serine-Threonine KinasesTreatment OutcomeVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsNon-small cell lung cancerTyrosine kinase inhibitorsVEGFR tyrosine kinase inhibitorsNSCLC cell linesZODIAC studyClinical benefitLung cancerPlatinum-refractory non-small cell lung cancerAdvanced non-small cell lung cancerImproved progression-free survivalDifferent lung cancersObjective response rateProgression-free survivalVEGF pathway inhibitorsCell lung cancerArchival tumor samplesCell linesActivation of mTORVandetanib armOverall survivalNSCLC modelsNSCLC cellsPreclinical studiesPatientsVEGFR inhibition
2015
E2F8 as a Novel Therapeutic Target for Lung Cancer
Park SA, Platt J, Lee JW, López-Giráldez F, Herbst RS, Koo JS. E2F8 as a Novel Therapeutic Target for Lung Cancer. Journal Of The National Cancer Institute 2015, 107: djv151. PMID: 26089541, PMCID: PMC4651101, DOI: 10.1093/jnci/djv151.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCCAAT-Enhancer-Binding ProteinsCell Line, TumorCell ProliferationCell SurvivalChromatin ImmunoprecipitationFluorescent Antibody TechniqueGene Expression Regulation, NeoplasticHumansImmunoblottingKaplan-Meier EstimateLung NeoplasmsMiceMolecular Targeted TherapyNeoplastic Stem CellsPromoter Regions, GeneticRepressor ProteinsTissue Array AnalysisUbiquitin-Protein LigasesUp-RegulationXenograft Model Antitumor AssaysConceptsTarget genesCell cycle regulationNovel therapeutic targetPromoter activity assaysCell proliferationCancer cellsExpression of UHRF1Transcription activatorAntisense morpholinoChromatin immunoprecipitationCycle regulationTherapeutic targetEmbryonic developmentE2F membersHuman lung cancer cellsMicroarray analysisInvasion analysisLung cancer cellsDirect bindingTumor growthE2F8Activity assaysPublic databasesColony formationUHRF1
2013
Evaluation of Novel Orthotopic Nude Mouse Models for Human Small-Cell Lung Cancer
Isobe T, Onn A, Morgensztern D, Jacoby JJ, Wu W, Shintani T, Itasaka S, Shibuya K, Koo PJ, O'Reilly MS, Herbst RS. Evaluation of Novel Orthotopic Nude Mouse Models for Human Small-Cell Lung Cancer. Journal Of Thoracic Oncology 2013, 8: 140-146. PMID: 23328546, DOI: 10.1097/jto.0b013e3182725ff9.Peer-Reviewed Original ResearchConceptsSmall cell lung cancerHuman small cell lung cancerLymph nodesLung cancerMurine modelOrthotopic nude mouse modelHuman SCLC tumorsAxillary lymph nodesOrthotopic murine modelNovel therapeutic strategiesSubcutaneous xenograft modelTumor growth patternNude mouse modelEffective murine modelLeft lungRight lungTumor sizeSolitary massSCLC tumorsOrthotopic modelMouse modelNew therapiesTherapeutic strategiesXenograft modelNude mice
2012
Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis
Takahashi O, Komaki R, Smith PD, Jürgensmeier JM, Ryan A, Bekele BN, Wistuba II, Jacoby JJ, Korshunova MV, Biernacka A, Erez B, Hosho K, Herbst RS, O'Reilly MS. Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis. Clinical Cancer Research 2012, 18: 1641-1654. PMID: 22275507, PMCID: PMC3306446, DOI: 10.1158/1078-0432.ccr-11-2324.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzimidazolesCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDisease ProgressionHumansLung NeoplasmsMaleMiceMice, NudeMitogen-Activated Protein KinasesMolecular Targeted TherapyNeovascularization, PathologicPaclitaxelProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsReceptors, Vascular Endothelial Growth FactorXenograft Model Antitumor AssaysConceptsSignal-regulated kinase kinaseTumor cell proliferationCell proliferationReceptor tyrosine kinasesKinase kinaseAvailable MEK1/2 inhibitorHuman NSCLC cellsTyrosine kinaseVEGF receptor tyrosine kinasesERK phosphorylationNCI-H441MEK1/2 inhibitorApoptotic effectsAdjacent normal tissuesKinaseNSCLC cellsMEK inhibitionAntiangiogenic effectsSignalingOrthotopic human lung cancer modelAvailable potent inhibitorLung tumor growthPotent inhibitorTumor angiogenesisSelumetinib
2007
Expression of epidermal growth factor (EGF)/transforming growth factor-α by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice
Wu W, O'Reilly MS, Langley RR, Tsan RZ, Baker CH, Bekele N, Tang XM, Onn A, Fidler IJ, Herbst RS. Expression of epidermal growth factor (EGF)/transforming growth factor-α by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice. Molecular Cancer Therapeutics 2007, 6: 2652-2663. PMID: 17913856, DOI: 10.1158/1535-7163.mct-06-0759.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAnimalsAntineoplastic AgentsBlotting, WesternCell ProliferationEpidermal Growth FactorErbB ReceptorsGefitinibGene DosageHumansLung NeoplasmsMaleMiceMice, NudePhosphorylationPurinesQuinazolinesReverse Transcriptase Polymerase Chain ReactionTransforming Growth Factor alphaXenograft Model Antitumor AssaysConceptsTumor-associated endothelial cellsEpidermal growth factor receptorTreatment of miceLung cancerEpidermal growth factorNCI-H441Endothelial cellsLung tumorsLigand expressionNon-small cell lung cancerExpression of EGFTumor cellsEGFR tyrosine kinase inhibitorsEGFR tyrosine kinase inhibitor gefitinibGrowth factorReceptor tyrosine kinase inhibitionTyrosine kinase inhibitor gefitinibLymph node metastasisCell lung cancerEGF receptor tyrosine kinase inhibitionLungs of miceHuman lung cancer cellsHuman lung cancerPrimary tumor growthTyrosine kinase inhibitorsTargeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer
Shibuya K, Komaki R, Shintani T, Itasaka S, Ryan A, Jürgensmeier JM, Milas L, Ang K, Herbst RS, O'Reilly MS. Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer. International Journal Of Radiation Oncology • Biology • Physics 2007, 69: 1534-1543. PMID: 17889445, PMCID: PMC2151850, DOI: 10.1016/j.ijrobp.2007.07.2350.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationCombined Modality TherapyDNA RepairEpidermal Growth FactorErbB ReceptorsFeasibility StudiesHumansLung NeoplasmsMaleMiceMice, NudeNeovascularization, PathologicPiperidinesPleural EffusionQuinazolinesRadiation ToleranceRadiation-Sensitizing AgentsReceptors, Vascular Endothelial Growth FactorVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsVascular endothelial growth factor receptor 2Epidermal growth factor receptorLung cancerHuman lung cancerOrthotopic modelRadiation therapyHuman lung adenocarcinoma cellsLung adenocarcinoma cellsConventional therapyAntitumor effectsOrthotopic human lung cancer modelNon-small cell lung cancerHuman non-small cell lung cancerHuman lung cancer modelAdenocarcinoma cellsGrowth factor receptor 2Lung tumor burdenLung cancer modelEndothelial growth factor receptor 2Pleural effusion formationFactor receptor 2Basic fibroblast growth factorMatrix metalloproteinase-2Human lung adenocarcinomaSublethal damage repairEndostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice
Itasaka S, Komaki R, Herbst RS, Shibuya K, Shintani T, Hunter NR, Onn A, Bucana CD, Milas L, Ang KK, O’Reilly M. Endostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice. International Journal Of Radiation Oncology • Biology • Physics 2007, 67: 870-878. PMID: 17293237, PMCID: PMC1976280, DOI: 10.1016/j.ijrobp.2006.10.030.Peer-Reviewed Original ResearchConceptsRadiation therapyConcurrent administrationTumor revascularizationDisease-free survivalVascular endothelial growth factorCombination of endostatinEffect of endostatinMatrix metalloproteinase-2Legs of miceEndothelial growth factorEndothelial cell apoptosisEndothelial cell proliferationAdvanced malignanciesA431 xenograftsClinical trialsInterleukin-8Antiangiogenic therapyAntiangiogenic agentsEpidermoid carcinomaPreclinical studiesHuman epidermoid carcinomaLeg tumorsTreatment groupsAntitumor effectsMetalloproteinase-2Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade
Wu W, Onn A, Isobe T, Itasaka S, Langley RR, Shitani T, Shibuya K, Komaki R, Ryan AJ, Fidler IJ, Herbst RS, O'Reilly MS. Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade. Molecular Cancer Therapeutics 2007, 6: 471-483. PMID: 17308046, DOI: 10.1158/1535-7163.mct-06-0416.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAngiogenesis InhibitorsAnimalsApoptosisBlotting, WesternCarcinoma, Squamous CellCell Line, TumorCell ProliferationEndothelium, VascularErbB ReceptorsFlow CytometryHumansLung NeoplasmsMaleMiceMice, Inbred BALB CMice, Inbred CBANeovascularization, PathologicPhosphorylationPiperidinesProto-Oncogene Proteins c-aktQuinazolinesSignal TransductionVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsVascular endothelial growth factorVEGF receptor 2EGF receptorEpidermal growth factorLung cancerHuman lung cancerEndothelial growth factorGrowth factorMitogen-activated protein kinaseNon-small cell lung cancerOrthotopic human lung cancerProtein tyrosine kinase inhibitorEndothelial cellsTumor-associated endothelial cellsHuman lung cancer specimensAdvanced lung cancerSelective protein tyrosine kinase inhibitorCell lung cancerLung cancer patientsOrthotopic mouse modelEndothelial cell tube formationLung cancer specimensHuman lung adenocarcinoma cellsTyrosine kinase inhibitorsSmall molecule inhibitors
2005
Erlotinib.
Herbst RS. Erlotinib. Clinical Advances In Hematology And Oncology 2005, 3: 125, 141. PMID: 16166980.Peer-Reviewed Original Research