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
2013
CXCR2 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
Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome
Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G. Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome. Journal Of The National Cancer Institute 2012, 104: 228-239. PMID: 22247021, PMCID: PMC3274509, DOI: 10.1093/jnci/djr523.Peer-Reviewed Original ResearchMeSH KeywordsAspartic AcidCarcinoma, Non-Small-Cell LungCell Line, TumorClinical Trials, Phase II as TopicCysteineDisease-Free SurvivalGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, rasGenetic VectorsGlycineHumansImmunoblottingImmunoprecipitationKaplan-Meier EstimateLentivirusLung NeoplasmsMicroarray AnalysisMolecular Targeted TherapyMutationProto-Oncogene Proteins c-aktRandomized Controlled Trials as TopicSignal TransductionTOR Serine-Threonine KinasesTreatment OutcomeValineConceptsNon-small cell lung cancerKirsten rat sarcoma viral oncogene homologProgression-free survivalNSCLC cell linesWild-type KrasMutant KrasRefractory non-small cell lung cancerWorse progression-free survivalRat sarcoma viral oncogene homologRas2 Kirsten rat sarcoma viral oncogene homologSarcoma viral oncogene homologKaplan-Meier curvesCell lung cancerReverse-phase protein array studiesKRas proteinsHuman bronchial epithelial cellsCancer cell growthPatient tumor samplesCell linesImmortalized human bronchial epithelial cellsBronchial epithelial cellsProtein array studiesTumor gene expressionEvaluable patientsClinical outcomes
2011
Increased VEGFR-2 Gene Copy Is Associated with Chemoresistance and Shorter Survival in Patients with Non–Small-Cell Lung Carcinoma Who Receive Adjuvant Chemotherapy
Yang F, Tang X, Riquelme E, Behrens C, Nilsson MB, Giri U, Varella-Garcia M, Byers LA, Lin HY, Wang J, Raso MG, Girard L, Coombes K, Lee JJ, Herbst RS, Minna JD, Heymach JV, Wistuba II. Increased VEGFR-2 Gene Copy Is Associated with Chemoresistance and Shorter Survival in Patients with Non–Small-Cell Lung Carcinoma Who Receive Adjuvant Chemotherapy. Cancer Research 2011, 71: 5512-5521. PMID: 21724587, PMCID: PMC3159530, DOI: 10.1158/0008-5472.can-10-2614.Peer-Reviewed Original ResearchConceptsCell lung carcinomaHIF-1α levelsAdjuvant therapyLung carcinomaAdjuvant platinum-based chemotherapyVEGFR-2 blockadeNuclear hypoxia inducible factor-1αNSCLC tumor cellsPlatinum-based chemotherapyFavorable overall survivalRisk of deathHypoxia-inducible factor-1αHigher microvessel densityNSCLC tumor specimensNSCLC cell linesInducible factor-1αCell linesVEGF receptor 2Adjuvant chemotherapyOverall survivalClinical outcomesAdenocarcinoma patientsMicrovessel densityShorter SurvivalHigh risk
2010
Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo
Meng J, Dai B, Fang B, Bekele BN, Bornmann WG, Sun D, Peng Z, Herbst RS, Papadimitrakopoulou V, Minna JD, Peyton M, Roth JA. Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo. PLOS ONE 2010, 5: e14124. PMID: 21124782, PMCID: PMC2993951, DOI: 10.1371/journal.pone.0014124.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBenzimidazolesCarcinoma, Non-Small-Cell LungCell CycleCell Line, TumorCell SurvivalDose-Response Relationship, DrugDrug SynergismFemaleHeterocyclic Compounds, 3-RingHumansLung NeoplasmsMiceMice, Inbred BALB CMice, NudeMitogen-Activated Protein Kinase KinasesProto-Oncogene Proteins c-aktSignal TransductionSurvival AnalysisTumor BurdenXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerCell lung cancerCombination of AZD6244Lung cancer cell linesCombination therapyLung cancerCancer cell linesTumor growthTumor tissueHuman non-small cell lung cancerLung cancer cell growthCell linesHuman lung cancer cell linesSingle drug treatmentSynergistic antitumor activityHuman lung tumorsAnimal survival timeMean animal survival timeCancer cell growthXenograft tumor growthP-AKT expressionLung tumorsDrug treatmentDrug combinationsSurvival time
2006
Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor
Green LJ, Marder P, Ray C, Cook CA, Jaken S, Musib LC, Herbst RS, Carducci M, Britten CD, Basche M, Eckhardt SG, Thornton D. Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor. Clinical Cancer Research 2006, 12: 3408-3415. PMID: 16740765, DOI: 10.1158/1078-0432.ccr-05-2231.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiomarkersCapecitabineCell Line, TumorClinical Trials, Phase I as TopicDeoxycytidineEnzyme ActivatorsEnzyme InhibitorsFlow CytometryFluorouracilFollow-Up StudiesHumansIndolesLeukocytes, MononuclearMonocytesNeoplasmsProtein Kinase CProtein Kinase C betaReproducibility of ResultsSensitivity and SpecificitySignal TransductionStructure-Activity RelationshipTreatment OutcomeConceptsPeripheral blood mononuclear cellsDaily oral dosesBlood mononuclear cellsCancer patientsOral dosesMononuclear cellsFlow cytometryDrug activity biomarkerPKC activityTarget cellsActivity biomarkersPhorbol esterNormal donorsPatientsActivity of PKCU937 cell lineTarget inhibitionEnzastaurinKinase inhibitorsΒ inhibitorSignificant decreaseCell linesU937 cellsIntracellular phosphoproteinsProtein kinase C
1997
Prostate carcinoma response to cytotoxic therapy: in vivo resistance.
Teicher BA, Kakeji Y, Ara G, Herbst RS, Northey D. Prostate carcinoma response to cytotoxic therapy: in vivo resistance. In Vivo 1997, 11: 453-61. PMID: 9509295.Peer-Reviewed Original ResearchConceptsPC-3 tumorsDU-145 tumorsTGF-beta mRNAPC-3 cellsDU-145 cellsLNCaP tumorsSingle dosesAndrogen-independent prostate cancerChemotherapy-resistant diseaseHuman prostate carcinoma cell linesConcentrations of melphalanIndependent prostate cancerProstate carcinoma cell linesProstate carcinoma xenograftsCytotoxic cancer therapyCell linesProstate cell linesVivo high levelsTime-dependent increaseChemotherapy administrationResistant diseaseCarcinoma cell linesCytotoxic therapyPlasma levelsCarcinoma responseTransforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin.
Teicher BA, Ikebe M, Ara G, Keyes SR, Herbst RS. Transforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin. In Vivo 1997, 11: 463-72. PMID: 9509296.Peer-Reviewed Original ResearchConceptsBone marrow CFU-GMMarrow CFU-GMAdministration of decorinParent tumorCFU-GMTumor linesBALB/c miceEffects of secretionsC micePlasma levelsVivo resistanceMonolayer culturesSolid tumorsTherapeutic resistanceTumorsTumor modelDrug resistanceDrug sensitivityDosage rangeThiotepaMelphalanCell linesCisplatinAdministrationAnimals
1991
Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells.
Herbst RS, Nielsch U, Sladek F, Lai E, Babiss LE, Darnell JE. Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells. The New Biologist 1991, 3: 289-96. PMID: 1878351.Peer-Reviewed Original ResearchMeSH KeywordsAlbuminsAnimalsBase SequenceCCAAT-Enhancer-Binding ProteinsDNADNA-Binding ProteinsGene Expression RegulationHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaHepatocyte Nuclear Factor 3-alphaHepatocyte Nuclear Factor 3-betaHepatocyte Nuclear Factor 3-gammaHepatocyte Nuclear Factor 4LiverMolecular Sequence DataNuclear ProteinsOligonucleotidesPhosphoproteinsPrealbuminRatsRNA, MessengerTranscription FactorsTumor Cells, CulturedConceptsTranscription factorsHepatocyte-enriched transcription factorsDNA-binding proteinsTransthyretin gene expressionRegulation of genesDNA-binding activityRat hepatoma cell lineLevel of expressionTranscriptional activityGene expressionHepatoma cell lineDifferential regulationCellular concentrationGenesHepatoma cellsCell linesExpressionRegulationTransthyretin geneLFB1HNF4HNF3ProteinEBPDifferent rates
1990
The state of cellular differentiation determines the activity of the adenovirus E1A enhancer element: evidence for negative regulation of enhancer function
Herbst RS, Pelletier M, Boczko EM, Babiss LE. The state of cellular differentiation determines the activity of the adenovirus E1A enhancer element: evidence for negative regulation of enhancer function. Journal Of Virology 1990, 64: 161-172. PMID: 2136708, PMCID: PMC249075, DOI: 10.1128/jvi.64.1.161-172.1990.Peer-Reviewed Original ResearchMeSH KeywordsAdenovirus Early ProteinsAdenoviruses, HumanAnimalsBase SequenceCell DifferentiationCell LineCell NucleusDNA-Binding ProteinsEnhancer Elements, GeneticGene ExpressionGene Expression Regulation, ViralGenes, ViralHeLa CellsHumansMolecular Sequence DataMutationOncogene Proteins, ViralPromoter Regions, GeneticRNA, MessengerSuppression, GeneticTranscription, GeneticViral Structural ProteinsConceptsE1A gene transcriptionFetal fibroblast cellsGene transcriptionHepatoma cell lineFibroblast cellsCell phenotypeCell linesLiver hepatocytesRodent hepatocytesRat liver hepatocytesSimilar binding activityFurther suppressionHeLa cellsEnhancer elementsCellsBinding activityHepatocytesViral genomeDifferentiated cellsE1A enhancerNegative regulationCellular differentiationImportant mechanismPhenotypeHigh levels