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 cellsThe 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
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 Research
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
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 increaseUpregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma
Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ, Park YY, Erez B, Jacoby JJ, Lee JS, Lin HY, Ciardiello F, Herbst RS, Langley RR, Heymach JV. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma. Journal Of Clinical Investigation 2011, 121: 1313-1328. PMID: 21436589, PMCID: PMC3070607, DOI: 10.1172/jci42405.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAngiogenesis InhibitorsAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedApoptosisBevacizumabCell Line, TumorDrug Resistance, NeoplasmErbB ReceptorsGene Expression ProfilingHumansLung NeoplasmsMaleMiceMice, NudeNeovascularization, PathologicRNA, MessengerRNA, NeoplasmStromal CellsUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsMouse xenograft modelHuman lung adenocarcinomaTumor cellsPrimary resistanceLung adenocarcinomaXenograft modelFGFR pathwayProgression-free survivalVEGF inhibitor bevacizumabEndothelium of tumorsInhibitors of angiogenesisCombination regimensTreatment of cancerVEGF inhibitorsPericyte coverageAntiangiogenic therapyVascular remodelingAngiogenesis inhibitorsTherapeutic efficacyTumor growthStromal pathwaysClinical useEGFRAcquired ResistanceEGFR pathway
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 timeMeasurement of conatumumab‐induced apoptotic activity in tumors by fine needle aspirate sampling
Zoog SJ, Y. C, Kaplan‐Lefko P, Hawkins JM, Moriguchi J, Zhou L, Pan Y, Hsu C, Friberg G, Herbst R, Hill J, Juan G. Measurement of conatumumab‐induced apoptotic activity in tumors by fine needle aspirate sampling. Cytometry Part A 2010, 77A: 849-860. PMID: 20623688, DOI: 10.1002/cyto.a.20940.Peer-Reviewed Original ResearchConceptsFine needle aspiratesDeath receptor 5Needle aspiratesNonsmall cell lung cancer patientsCell lung cancer patientsCaspase-3 activationLung cancer patientsTumor necrosis factorCaspase-3Tumor-bearing miceTumor cell deathReceptor therapyPharmacodynamic markersCancer patientsDrug exposureClinical trialsCaspase 3/7 activityNecrosis factorColo205 xenograftsClinical investigationReceptor 5FNA biopsyTumor typesPharmacological impactClinical settingTreatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice
Jacoby JJ, Erez B, Korshunova MV, Williams RR, Furutani K, Takahashi O, Kirkpatrick L, Lippman SM, Powis G, O'Reilly MS, Herbst RS. Treatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice. Journal Of Thoracic Oncology 2010, 5: 940-949. PMID: 20512076, PMCID: PMC3782111, DOI: 10.1097/jto.0b013e3181dc211f.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAnimalsApoptosisBlotting, WesternCarcinoma, Non-Small-Cell LungDisease ProgressionHumansHypoxia-Inducible Factor 1, alpha SubunitImmunoenzyme TechniquesLung NeoplasmsLymphatic MetastasisMaleMiceMice, NudeMustard CompoundsPhenylpropionatesSmall Cell Lung CarcinomaSurvival RateTreatment OutcomeTumor Cells, CulturedConceptsLung tumor volumePX-478Tumor volumeLung cancerNSCLC modelsLung adenocarcinomaNon-small cell lung cancer xenograftsSmall cell lung cancer modelCell lung cancer xenograftsHuman small cell lung cancerSmall cell lung cancerCell lung cancer modelsPhase I clinical trialPX-478 treatmentAntitumor activityDaily oral treatmentMedian survival durationVehicle-treated groupCell lung cancerLung cancer xenograftsLung cancer patientsLung adenocarcinoma cell modelsLung cancer cell linesLung cancer modelOrthotopic mouse modelMolecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor
Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L, Herbst R, Jacoby JJ, Zhou LL, Ahad AM, Mash EA, Kirkpatrick DL, Powis G. Molecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor. Molecular Cancer Therapeutics 2010, 9: 706-717. PMID: 20197390, PMCID: PMC2837366, DOI: 10.1158/1535-7163.mct-09-0985.Peer-Reviewed Original ResearchMeSH Keywords3-Phosphoinositide-Dependent Protein KinasesAnimalsAntineoplastic AgentsFemaleHumansMiceMice, Inbred C57BLMice, NudeModels, BiologicalOncogene Protein v-aktProtein BindingProtein Interaction Domains and MotifsProtein Kinase InhibitorsProtein Serine-Threonine KinasesSulfonamidesThiadiazolesTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsAntitumor activityTumor xenograftsNon-small cell lung cancerMolecular pharmacologyCell lung cancerAdditive antitumor activityHuman tumor xenograftsPHT-427K-ras mutant tumorsVivo antitumor activityLung cancerSensitive tumorsPIK3CA mutationsBreast cancerImmunodeficient miceBlood chemistryMutant tumorsCombination studiesResistant cellsMinimal toxicityWeight lossTumorsCancerCancer cellsAkt inhibition
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 inhibitors