2022
Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)
Atkins MB, Abu-Sbeih H, Ascierto PA, Bishop MR, Chen DS, Dhodapkar M, Emens LA, Ernstoff MS, Ferris RL, Greten TF, Gulley JL, Herbst RS, Humphrey RW, Larkin J, Margolin KA, Mazzarella L, Ramalingam SS, Regan MM, Rini BI, Sznol M. Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC). Journal For ImmunoTherapy Of Cancer 2022, 10: e005413. PMID: 36175037, PMCID: PMC9528604, DOI: 10.1136/jitc-2022-005413.Peer-Reviewed Original ResearchConceptsPhase III trialsImmunotherapy of cancerIII trialsCurative responseImmune checkpoint inhibitor monotherapyCell death protein 1Checkpoint inhibitor monotherapyDefinitive predictive biomarkersDurable clinical benefitProgression-free survivalMinority of patientsDeath protein 1Variety of indicationsClinical trial designAnimal tumor modelsLimited Phase IDrug development programsImmunotherapy combinationsInvestigational chemotherapyImmunotherapy fieldInhibitor monotherapyOverall survivalDismal prognosisClinical benefitSurvival outcomes
2021
A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy
Sanmamed MF, Nie X, Desai SS, Villaroel-Espindola F, Badri T, Zhao D, Kim AW, Ji L, Zhang T, Quinlan E, Cheng X, Han X, Vesely MD, Nassar AF, Sun J, Zhang Y, Kim TK, Wang J, Melero I, Herbst RS, Schalper KA, Chen L. A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy. Cancer Discovery 2021, 11: 1700-1715. PMID: 33658301, PMCID: PMC9421941, DOI: 10.1158/2159-8290.cd-20-0962.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerTumor-infiltrating lymphocytesExhausted T cellsTIL subsetsTumor microenvironmentCancer immunotherapyT cellsAdvanced non-small cell lung cancerPatient-derived tumor xenograft modelAnti-PD therapyT cell subsetsCell lung cancerPotential tissue biomarkersBaseline tumor tissueLung cancer tissuesSingle-cell mass cytometryTumor xenograft modelApoptotic CD8Dysfunctional CD8Immunotherapy resistancePD-1Activation markersAdjacent nontumoral tissuesPathway-dependent mannerLung cancer
2019
Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Dong MB, Wang G, Chow RD, Ye L, Zhu L, Dai X, Park JJ, Kim HR, Errami Y, Guzman CD, Zhou X, Chen KY, Renauer PA, Du Y, Shen J, Lam SZ, Zhou JJ, Lannin DR, Herbst RS, Chen S. Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells. Cell 2019, 178: 1189-1204.e23. PMID: 31442407, PMCID: PMC6719679, DOI: 10.1016/j.cell.2019.07.044.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCD8-Positive T-LymphocytesCell Line, TumorClustered Regularly Interspaced Short Palindromic RepeatsCytokinesFemaleHumansImmunologic MemoryImmunotherapyMaleMiceMice, KnockoutNF-kappa BProgrammed Cell Death 1 ReceptorRNA HelicasesRNA, Guide, CRISPR-Cas SystemsTranscriptomeConceptsCRISPR screensTarget discoveryGenome-scale CRISPR screensCD8 TRNA helicase DHX37Vivo CRISPR screensGenetic screenGenome scaleTranscriptomic profilingBiochemical interrogationAntigen-specific CD8 TAnti-tumor immune responseFunctional regulatorTriple-negative breast cancerDHX37Essential roleTim-3PD-1Cytokine productionTumor infiltrationImmunotherapy targetImmunotherapy settingsRegulatorBreast cancerT cellsSiglec-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 ablationThe Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer
Lee JW, Zhang Y, Eoh KJ, Sharma R, Sanmamed MF, Wu J, Choi J, Park HS, Iwasaki A, Kaftan E, Chen L, Papadimitrakopoulou V, Herbst RS, Koo JS. The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer. Journal Of Thoracic Oncology 2019, 14: 1046-1060. PMID: 30771521, PMCID: PMC6542636, DOI: 10.1016/j.jtho.2019.02.004.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma of LungAnimalsAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenDrug SynergismFemaleLung NeoplasmsMAP Kinase Kinase KinasesMiceMice, KnockoutMice, TransgenicMyeloid-Derived Suppressor CellsProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)PyridonesPyrimidinonesSurvival AnalysisTumor Suppressor Protein p53ConceptsImmune cell populationsLung tumorsMEK inhibitorsDeath-1Survival outcomesLung cancerL1 mAbsTumor-infiltrating immune cell populationsTumor-infiltrating immune cellsCell death ligand 1Flow cytometryLung cancer mouse modelAdenoviral Cre recombinaseAutochthonous lung tumorsImmunomodulatory monoclonal antibodiesTumor-infiltrating CD8PD-L1 expressionSingle-agent therapyTumor-bearing lungsDeath ligand 1Tumor-free miceLung cancer modelCombinatorial antitumor effectCancer mouse modelCell populations
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
2017
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Cascone T, Xu L, Lin HY, Liu W, Tran HT, Liu Y, Howells K, Haddad V, Hanrahan E, Nilsson MB, Cortez MA, Giri U, Kadara H, Saigal B, Park YY, Peng W, Lee JS, Ryan AJ, Jüergensmeier JM, Herbst RS, Wang J, Langley RR, Wistuba II, Lee JJ, Heymach JV. The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer. Clinical Cancer Research 2017, 23: 5489-5501. PMID: 28559461, PMCID: PMC5600821, DOI: 10.1158/1078-0432.ccr-16-3216.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarcinoma, Non-Small-Cell LungCell Line, TumorClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDisease Models, AnimalDrug Resistance, NeoplasmGene Expression ProfilingHepatocyte Growth FactorHumansHypoxiaKaplan-Meier EstimateLung NeoplasmsMaleMiceMolecular Targeted TherapyMulticenter Studies as TopicNeovascularization, PathologicPrognosisProtein Kinase InhibitorsProto-Oncogene Proteins c-metReceptors, Vascular Endothelial Growth FactorSignal TransductionXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerHepatocyte growth factorC-MetHGF/c-Met pathwayHuman non-small cell lung cancerResistance of NSCLCAngiogenic factor levelsHGF plasma levelsCancer cellsTumor microvascular densityCell lung cancerEffect of therapyTortuous blood vesselsTumor vascular bedC-Met pathwayTyrosine kinase inhibitorsTumor-associated stromaClin Cancer ResHuman lung adenocarcinomaMurine xenograft modelVEGFR-TKIClinical outcomesLung cancerPlasma levelsMicrovascular densityLung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis
Korde A, Jin L, Zhang JG, Ramaswamy A, Hu B, Kolahian S, Guardela BJ, Herazo-Maya J, Siegfried JM, Stabile L, Pisani MA, Herbst RS, Kaminski N, Elias JA, Puchalski JT, Takyar SS. Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis. American Journal Of Respiratory And Critical Care Medicine 2017, 196: 1443-1455. PMID: 28853613, PMCID: PMC5736970, DOI: 10.1164/rccm.201610-2157oc.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerMiR-1 levelsLewis lung carcinoma xenograftsLung carcinoma xenograftsTransgenic miceEndothelial cellsNSCLC tumorsCarcinoma xenograftsLung endotheliumMiR-1Tumor growthTumor progressionVascular endothelial cadherin promoterMicroRNA-1Cohort of patientsTumor-bearing lungsCell lung cancerVascular endothelial growth factorCancer-free tissuesEndothelial growth factorInducible transgenic miceMiR-1 overexpressionKP miceOverall survivalTumor burdenExtracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases
Stevens LE, Cheung WKC, Adua SJ, Arnal-Estapé A, Zhao M, Liu Z, Brewer K, Herbst RS, Nguyen DX. Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases. Cancer Research 2017, 77: 1905-1917. PMID: 28196904, PMCID: PMC5468792, DOI: 10.1158/0008-5472.can-16-1978.Peer-Reviewed Original ResearchConceptsBrain metastatic nicheRisk of relapseDistant metastasisPoor prognosisLUAD subtypesLung tumorsLung adenocarcinomaLUAD cellsMetastatic outgrowthMetastatic nicheCancer ResCancer cellsECM-mediated signalingExtracellular matrix moleculesCell survivalMolecular signaturesDifferential expressionHMMRMatrix moleculesImportant mechanismCellsRelapseAdenocarcinomaPrognosisMetastasis
2016
GSK-3α Is a Novel Target of CREB and CREB-GSK-3α Signaling Participates in Cell Viability in Lung Cancer
Park SA, Lee JW, Herbst RS, Koo JS. GSK-3α Is a Novel Target of CREB and CREB-GSK-3α Signaling Participates in Cell Viability in Lung Cancer. PLOS ONE 2016, 11: e0153075. PMID: 27049759, PMCID: PMC4822949, DOI: 10.1371/journal.pone.0153075.Peer-Reviewed Original ResearchImmune checkpoint therapy for non-small-cell lung cancer: an update
Xia B, Herbst RS. Immune checkpoint therapy for non-small-cell lung cancer: an update. Immunotherapy 2016, 8: 279-298. PMID: 26860624, DOI: 10.2217/imt.15.123.Peer-Reviewed Original ResearchConceptsCell lung cancerImmune checkpointsLung cancerCo-inhibitory immune checkpointsRole of immunotherapyImmune checkpoint therapyImmune checkpoint pathwaysSynergistic antitumor activityCheckpoint inhibitorsInhibitory checkpointsCheckpoint therapyL1 antibodyImmune cellsNovel therapiesImmune activityAntagonist antibodyTumor growthTumor microenvironmentTumor cellsTherapyAntitumor activityAntibodiesCancerImmunotherapyCells
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 formationUHRF1Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis
Ma B, Herzog EL, Lee CG, Peng X, Lee CM, Chen X, Rockwell S, Koo JS, Kluger H, Herbst RS, Sznol M, Elias JA. Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis. Cancer Research 2015, 75: 487-496. PMID: 25511377, PMCID: PMC4321965, DOI: 10.1158/0008-5472.can-13-3339.Peer-Reviewed Original ResearchConceptsMelanoma lung metastasisPulmonary melanoma metastasesPulmonary metastasesLung metastasesMelanoma metastasesGenetic deletionBreast cancer cellsPlexin C1 receptorsPulmonary microenvironmentPoor prognosisSemaphorin 7AMelanoma spreadChitinase 3MetastasisCHI3L1Cancer progressionSema7AInhibitory wayCancer cellsReceptorsSignificant reductionΒ1 integrinNovel pathwayCritical roleIL13Rα2
2014
Emerging Science and Therapies in Non-small-Cell Lung Cancer: Targeting the MET Pathway
Kris MG, Arenberg DA, Herbst RS, Riely GJ. Emerging Science and Therapies in Non-small-Cell Lung Cancer: Targeting the MET Pathway. Clinical Lung Cancer 2014, 15: 475. PMID: 25306384, DOI: 10.1016/j.cllc.2014.08.001.Peer-Reviewed Original ResearchConceptsCell lung cancerLung cancerMET pathwayNon-small cell lung cancerCME activitiesProgression-free survivalLung cancer patientsLung cancer specialistsCare of patientsIndividualized treatment strategiesLung cancer mutationsClinical research advancesQuality of lifeCollection of diseasesFree survivalMedical oncologistsCancer patientsCancer specialistsPatient outcomesTreatment strategiesHealthcare cliniciansCancer cell mutationsPatientsTissue acquisitionMET expressionThe PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer
Henick BS, Herbst RS, Goldberg SB. The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer. Expert Opinion On Therapeutic Targets 2014, 18: 1407-1420. PMID: 25331677, DOI: 10.1517/14728222.2014.955794.Peer-Reviewed Original ResearchConceptsPD-1 pathwayEarly clinical trialsClinical trialsTumor typesDeath-1 pathway inhibitorsPD-1 pathway inhibitionImmune escape mechanismsOngoing clinical trialsEarly-stage cancerTreatment of cancerCure rateLikely respondersCancer immunotherapyPreclinical dataAntineoplastic effectsTherapeutic targetPathway inhibitionPathway inhibitorCancer typesBiological rationaleCancer treatmentMonoclonal antibodiesEscape mechanismsUpcoming trialsTrials
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 miceCXCR2 Expression in Tumor Cells Is a Poor Prognostic Factor and Promotes Invasion and Metastasis in Lung Adenocarcinoma
Saintigny P, Massarelli E, Lin S, Ahn YH, Chen Y, Goswami S, Erez B, O'Reilly MS, Liu D, Lee JJ, Zhang L, Ping Y, Behrens C, Soto L, Heymach JV, Kim ES, Herbst RS, Lippman SM, Wistuba II, Hong WK, Kurie JM, Koo JS. CXCR2 Expression in Tumor Cells Is a Poor Prognostic Factor and Promotes Invasion and Metastasis in Lung Adenocarcinoma. Cancer Research 2013, 73: 571-582. PMID: 23204236, PMCID: PMC3548940, DOI: 10.1158/0008-5472.can-12-0263.Peer-Reviewed Original ResearchConceptsGene expression profilesNon-small cell lung cancerKnockdown clonesNSCLC cell linesHuman NSCLC cell linesExpression profilesCell linesStable knockdown clonesLung adenocarcinomaLung adenocarcinoma cell linesTumor cellsRAS pathway activationCXCR2 expressionPoor prognosisLung cancer cellsOrthotopic syngeneic mouse modelAdenocarcinoma cell linePromotes InvasionExpression of CXCL5Role of CXCR2Poor prognostic factorCell lung cancerPromoter methylationSyngeneic mouse modelProtein expressionAn Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV. An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance. Clinical Cancer Research 2013, 19: 279-290. PMID: 23091115, PMCID: PMC3567921, DOI: 10.1158/1078-0432.ccr-12-1558.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxl Receptor Tyrosine KinaseCarcinoma, Non-Small-Cell LungCell Line, TumorCluster AnalysisDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionErbB ReceptorsGene Expression ProfilingHumansLung NeoplasmsMiceNeoplasm MetastasisPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProteomeProteomicsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesRecurrenceReproducibility of ResultsConceptsEpithelial-mesenchymal transitionPotential therapeutic targetEGFR inhibitor resistanceTherapeutic targetEMT signatureInhibitor resistanceMesenchymal transition gene signatureMesenchymal cellsCell linesBiomarker-Integrated ApproachesPI3K/Akt pathway inhibitorNon-small cell lung carcinoma cell lineEGFR mutation statusReceptor tyrosine kinase AXLNSCLC cell linesPI3K/Akt inhibitorCell lung carcinoma cell lineGene expression profilesTyrosine kinase AXLLung carcinoma cell linePI3K inhibitorsDrug response analysisAkt pathway inhibitorCarcinoma cell linesErlotinib resistance
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
2011
Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours
Pan Y, Xu R, Peach M, Huang CP, Branstetter D, Novotny W, Herbst RS, Eckhardt SG, Holland PM. Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours. British Journal Of Cancer 2011, 105: 1830-1838. PMID: 22033270, PMCID: PMC3251880, DOI: 10.1038/bjc.2011.456.Peer-Reviewed Original ResearchConceptsCell death markersAdvanced tumorsPharmacodynamic biomarkersApoptotic markersPhase 1a studyPhase 1a trialDeath receptors DR4Colo205 tumorsSerum 8Patients 24Active caspase-3Patient seraColo205 xenograftsEvidence of activitySubsequent cell deathCytokeratin 18PatientsTransient increaseDulanerminReceptors DR4TumorsCaspase-3SerumCaspase-3/7Significant increase