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 burden
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
Upregulated 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
2009
Tumor Blood Flow Measured by Perfusion Computed Tomography and 15O-Labeled Water Positron Emission Tomography
Ng CS, Kodama Y, Mullani NA, Barron BJ, Wei W, Herbst RS, Abbruzzese JL, Charnsangavej C. Tumor Blood Flow Measured by Perfusion Computed Tomography and 15O-Labeled Water Positron Emission Tomography. Journal Of Computer Assisted Tomography 2009, 33: 460-465. PMID: 19478644, DOI: 10.1097/rct.0b013e318182d2e0.Peer-Reviewed Original ResearchConceptsWater positron emission tomographyPositron emission tomographyBlood flowEmission tomographyMean blood flow valuesBlood flow estimatesPerfusion Computed TomographyTumor blood flowPairs of examinationsBlood flow valuesMixed regression analysesUse of PCTBlood flow measurementsClinical gold standardIndex tumorClinical studiesComputed tomographySolid tumorsTumorsGold standardBland-AltmanTomographySignificant differencesRegression analysisT-test
2008
Lung Cancer
Herbst RS, Heymach JV, Lippman SM. Lung Cancer. New England Journal Of Medicine 2008, 359: 1367-1380. PMID: 18815398, PMCID: PMC10662965, DOI: 10.1056/nejmra0802714.Peer-Reviewed Original ResearchSummary Report 7th Annual Targeted Therapies of the Treatment of Lung Cancer
Einhorn LH, Bonomi P, Bunn PA, Camidge DR, Carbone DP, Choy H, Dubinett SM, Gandara DR, Gaspar LE, Govindan R, Johnson DH, Minna JD, Scagliotti G, West HJ, Herbst RS. Summary Report 7th Annual Targeted Therapies of the Treatment of Lung Cancer. Journal Of Thoracic Oncology 2008, 3: 545-555. PMID: 18449013, PMCID: PMC3374724, DOI: 10.1097/jto.0b013e318170627f.Peer-Reviewed Original ResearchCurrent and Future Strategies for Antiangiogenic Agents in Non–Small-Cell Lung Cancer
Herbst RS. Current and Future Strategies for Antiangiogenic Agents in Non–Small-Cell Lung Cancer. Clinical Lung Cancer 2008, 9: s50. PMID: 21884998, DOI: 10.3816/clc.2008.s.007.Peer-Reviewed Original ResearchMultitargeted Inhibitors in Lung Cancer: New Clinical Data
Bar J, Herbst RS, Onn A. Multitargeted Inhibitors in Lung Cancer: New Clinical Data. Clinical Lung Cancer 2008, 9: s92-s99. PMID: 19419930, DOI: 10.3816/clc.2008.s.014.Peer-Reviewed Original ResearchConceptsLung cancerManagement of patientsCell lung cancerOngoing clinical trialsNew clinical dataCombination of therapiesTreatment arsenalMultitargeted therapyClinical trialsNovel therapiesClinical dataNovel agentsRadiation therapyTraditional chemotherapyTherapyCancerClinical useMalignant growthMultitargeted inhibitorsTreatmentPathwayMajor pathwayChemotherapyPatientsAgents
2007
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
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 repairAngiogenesis and lung cancer: implications for prognosis and treatment
Onn A, Herbst RS. Angiogenesis and lung cancer: implications for prognosis and treatment. The Lancet Oncology 2007, 8: 460-461. PMID: 17540301, DOI: 10.1016/s1470-2045(07)70153-5.Peer-Reviewed Original ResearchEndostatin 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 inhibitorsVandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
Herbst RS, Heymach JV, O’Reilly M, Onn A, Ryan AJ. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opinion On Investigational Drugs 2007, 16: 239-249. PMID: 17243944, DOI: 10.1517/13543784.16.2.239.Peer-Reviewed Original ResearchConceptsTumor typesHereditary medullary thyroid cancerReceptor tyrosine kinase inhibitorsPhase III trialsProgression-free survivalDaily oral administrationPhase II evaluationPhase I studiesMedullary thyroid cancerTyrosine kinase inhibitorsSolid tumor typesTumor cell proliferationRefractory NSCLCAdvanced NSCLCIII trialsI studiesII evaluationThyroid cancerOral administrationAvailable agentsClinical developmentPharmacokinetic profileTumor growthVandetanibTumor angiogenesis
2006
Angiogenesis inhibition in the treatment of lung cancer.
Vokes E, Herbst R, Sandler A. Angiogenesis inhibition in the treatment of lung cancer. Clinical Advances In Hematology And Oncology 2006, 4: 1-10; quiz 11-2. PMID: 17143257.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabCarboplatinCarcinoma, Non-Small-Cell LungClinical Trials, Phase III as TopicDisease-Free SurvivalErlotinib HydrochlorideHemorrhageHumansLung NeoplasmsNeovascularization, PathologicPaclitaxelProtein Kinase InhibitorsQuinazolinesRandomized Controlled Trials as TopicRisk FactorsSurvival RateVascular Endothelial Growth Factor AConceptsNon-small cell lung cancerVascular endothelial growth factorLung cancerAntiangiogenic therapyNon-squamous cell non-small cell lung cancerAnti-VEGF monoclonal antibody bevacizumabSmall molecule tyrosine kinase inhibitorsRandomized phase II studyRandomized phase III trialEpidermal growth factor receptor inhibitor erlotinibPhase II studyAddition of bevacizumabPhase III trialsSignificant survival benefitCell lung cancerSignificant clinical benefitMonoclonal antibody bevacizumabComprehensive treatment approachTyrosine kinase inhibitorsEndothelial growth factorImportant therapeutic targetOngoing studiesNSCLC settingBevacizumab treatmentII studyTherapeutic options to target angiogenesis in human malignancies
Herbst RS. Therapeutic options to target angiogenesis in human malignancies. Expert Opinion On Emerging Drugs 2006, 11: 635-650. PMID: 17064223, DOI: 10.1517/14728214.11.4.635.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAntineoplastic AgentsDrug Delivery SystemsHumansNeoplasmsNeovascularization, PathologicConceptsTyrosine kinase inhibitorsHuman malignanciesMonoclonal antibodiesGrowth factorKinase inhibitorsAnti-VEGF inhibitorsGastrointestinal stromal tumorsSolid human malignanciesRenal cell carcinomaBasic fibroblast growth factorRole of VEGFTypes of cancerFibroblast growth factorStromal tumorsTherapeutic optionsCell carcinomaColorectal cancerAntiangiogenic drugsClinical trialsDrug classesPro-angiogenic growth factorsSmall molecule inhibitorsTumor growthTumor angiogenesisMatrix breakdown
2005
Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results
Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G. Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results. Journal Of Clinical Oncology 2005, 23: 5474-5483. PMID: 16027439, DOI: 10.1200/jco.2005.04.192.Peer-Reviewed Original ResearchConceptsAdvanced solid tumorsAG-013736Clinical activityOral receptor tyrosine kinase inhibitorSolid tumorsReceptor tyrosine kinase inhibitorsGrowth factorSingle test dosesMaximum-tolerated dosePhase II doseDose-limiting toxicitySignificant drug interactionsPeak plasma concentrationEndothelial cell growth factorPhase II testingVascular endothelial cell growth factorTyrosine kinase inhibitorsHighest dose levelPlatelet-derived growth factorIndividual PK parametersEffect of foodCell growth factorObserved hypertensionDrug holidayPartial responseDynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study
Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, Jackson E, Kelcz F, Yeh BM, Lee FT, Charnsangavej C, Park JW, Ashton EA, Steinfeldt HM, Pithavala YK, Reich SD, Herbst RS. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study. Journal Of Clinical Oncology 2005, 23: 5464-5473. PMID: 16027440, DOI: 10.1200/jco.2005.04.143.Peer-Reviewed Original ResearchConceptsAdvanced solid tumorsAG-013736Vascular responsesMagnetic resonance imagingAcute dosingDay 2Solid tumorsAngiogenesis inhibitorsResonance imagingContrast-enhanced magnetic resonance imagingOral angiogenesis inhibitorSchedule of therapyTumor vascular functionDynamic contrast-enhanced magnetic resonance imagingObjective disease responsePhase II testingDCE-MRI scansEffect of treatmentTumor vascular parametersVolume transfer constantMorning doseSuitable markerPharmacodynamic measuresVascular functionPharmacodynamic responseRole of novel targeted therapies in the clinic
Herbst RS. Role of novel targeted therapies in the clinic. British Journal Of Cancer 2005, 92: s21-s27. PMID: 15928655, PMCID: PMC2362061, DOI: 10.1038/sj.bjc.6602605.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntineoplastic AgentsClinical Trials as TopicErbB ReceptorsHumansNeoplasmsNeovascularization, PathologicPatient SelectionReceptors, Vascular Endothelial Growth FactorAngiogenesis and lung cancer: prognostic and therapeutic implications.
Herbst RS, Onn A, Sandler A. Angiogenesis and lung cancer: prognostic and therapeutic implications. Journal Of Clinical Oncology 2005, 23: 3243-56. PMID: 15886312, DOI: 10.1200/jco.2005.18.853.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorAntiangiogenic agentsLung cancerSurrogate markerProangiogenic vascular endothelial growth factorMajority of patientsReliable surrogate markerTumor vascular developmentDownstream receptor signalingKey therapeutic strategyEndothelial growth factorVEGF receptor bindingMetastatic diseaseMost patientsCancer deathConventional chemotherapyCommon causeTherapeutic strategiesTherapeutic implicationsTumor typesTumor vasculatureTarget inhibitionAnticancer effectsCytostatic effectReceptor signaling