2023
Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor
McNamara B, Harold J, Manavella D, Bellone S, Mutlu L, Hartwich T, Zipponi M, Yang-Hartwich Y, Demirkiran C, Verzosa M, Yang K, Choi J, Dong W, Buza N, Hui P, Altwerger G, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Burton E, Inagaki H, Albers A, Zhang C, Bollag G, Schlessinger J, Santin A. Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor. Gynecologic Oncology 2023, 172: 65-71. PMID: 36958197, PMCID: PMC10192120, DOI: 10.1016/j.ygyno.2023.03.009.Peer-Reviewed Original ResearchConceptsUterine leiomyosarcomaPDX modelsGain of functionMedian overall survivalPhase I trialOral gavage dailyVivo activityTumor growth inhibitionTumor volume differencesTumor cell proliferationOverall survivalTolerable toxicityI trialOral treatmentTreatment cohortsGavage dailyAggressive tumorsSCID miceULMS patientsPK studiesTumor samplesWestern blotCell proliferationControl vehicleLeiomyosarcoma
2019
HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy
Rottmann D, Snir OL, Wu X, Wong S, Hui P, Santin AD, Buza N. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Modern Pathology 2019, 33: 118-127. PMID: 31477811, DOI: 10.1038/s41379-019-0358-x.Peer-Reviewed Original ResearchConceptsEndometrial serous carcinomaHER2-positive tumorsSerous carcinomaSarcoma componentHER2 statusGynecologic carcinosarcomaHER2 expression/amplificationRecent phase II clinical trialPhase II clinical trialCarboplatin-paclitaxel chemotherapyEquivocal HER2 expressionProgression-free survivalAppropriate patient selectionExpression/amplificationFemale genital tractMembranous staining patternHER2 protein expressionHER2 immunohistochemical scoresUterine primaryDismal prognosisPatient selectionCarcinoma componentMixed carcinomasHER2 expressionClinical trials
2017
Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo
Menderes G, Bonazzoli E, Bellone S, Black JD, Lopez S, Pettinella F, Masserdotti A, Zammataro L, Litkouhi B, Ratner E, Silasi DA, Azodi M, Schwartz PE, Santin AD. Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo. Medical Oncology 2017, 34: 91. PMID: 28397106, PMCID: PMC5896014, DOI: 10.1007/s12032-017-0956-8.Peer-Reviewed Original ResearchConceptsEpithelial ovarian carcinomaOvarian carcinoma xenograftsOvarian cancerOvarian carcinomaCarcinoma xenograftsPreclinical efficacyCell linesTumor cell linesHER2/neu expressionChemotherapy-resistant diseaseOvarian cancer cell linesAvailable treatment strategiesEfficacy of neratinibInhibits xenograft growthNovel therapeutic agentsPrimary tumor cell linesG0/G1 phaseCell cycle distributionCell signaling changesNeratinib treatmentCancer cell linesGynecologic malignanciesOverall survivalNeu expressionClinical trials
2015
Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo
Lopez S, Cocco E, Black J, Bellone S, Bonazzoli E, Predolini F, Ferrari F, Schwab CL, English DP, Ratner E, Silasi DA, Azodi M, Schwartz PE, Terranova C, Angioli R, Santin AD. Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo. Molecular Cancer Therapeutics 2015, 14: 2519-2526. PMID: 26333383, PMCID: PMC4636465, DOI: 10.1158/1535-7163.mct-15-0383.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsCell CycleCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesCystadenocarcinoma, SerousDose-Response Relationship, DrugDrug SynergismFemaleGene AmplificationHumansImidazolesImmunoblottingMice, SCIDMutationOxazepinesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationQuinolinesReceptor, ErbB-2Uterine NeoplasmsXenograft Model Antitumor AssaysConceptsHER2/neu gene amplificationNeu gene amplificationUSC xenograftsUterine serous carcinomaGene amplificationUterine serous carcinoma cell linesSingle-agent therapyNovel therapeutic optionsWild-type PIK3CADose-dependent increaseIdeal therapeutic targetUSC cell linesCell linesDose-dependent declineFlow cytometry assayG0-G1 phaseCell cycle distributionOncogenic PIK3CA mutationsPercentage of cellsUSC patientsEndometrial cancerAggressive variantSerous carcinomaTherapeutic optionsCarcinoma cell linesPIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas
Black JD, Lopez S, Cocco E, Bellone S, Altwerger G, Schwab CL, English DP, Bonazzoli E, Predolini F, Ferrari F, Ratner E, Silasi DA, Azodi M, Schwartz PE, Santin AD. PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas. British Journal Of Cancer 2015, 113: 1020-1026. PMID: 26325104, PMCID: PMC4651122, DOI: 10.1038/bjc.2015.306.Peer-Reviewed Original ResearchConceptsUSC cell linesCell linesPIK3CA-mutated tumorsUterine serous carcinomaHER2/neuXenograft mouse modelOncogenic PIK3CA mutationsPrimary HER2Trastuzumab treatmentSerous carcinomaCarcinoma cell linesMechanisms of resistancePIK3CA mutationsTrastuzumab efficacyMouse modelTrastuzumabMouse xenograftsHER2Tumor growthMajor mechanismOncogenic mutationsWild-type cell linesSitu hybridisationNeratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo
Schwab CL, English DP, Black J, Bellone S, Lopez S, Cocco E, Bonazzoli E, Bussi B, Predolini F, Ferrari F, Ratner E, Silasi DA, Azodi M, Rutherford T, Schwartz PE, Santin AD. Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo. Gynecologic Oncology 2015, 139: 112-117. PMID: 26260909, PMCID: PMC4587290, DOI: 10.1016/j.ygyno.2015.08.002.Peer-Reviewed Original ResearchConceptsHER2/neuTreatment of HER2Efficacy of neratinibCarcinosarcoma cell lineTumor growthCell linesEffective treatment optionDeadliest gynecologic malignancyG0/G1 phaseCell cycle distributionCell signaling changesActivation of S6Neratinib treatmentGynecologic malignanciesOverall survivalTreatment optionsClinical trialsXenograft growthNew therapiesHER2NeratinibFlow cytometryNeuCycle distributionSignaling changesDacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro
Zhu L, Lopez S, Bellone S, Black J, Cocco E, Zigras T, Predolini F, Bonazzoli E, Bussi B, Stuhmer Z, Schwab CL, English DP, Ratner E, Silasi DA, Azodi M, Schwartz PE, Rutherford TJ, Santin AD. Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro. Tumor Biology 2015, 36: 5505-5513. PMID: 25669172, PMCID: PMC5573583, DOI: 10.1007/s13277-015-3218-4.Peer-Reviewed Original ResearchConceptsUterine serous carcinomaReceptor tyrosine kinase inhibitorsHER2/neu gene amplificationTyrosine kinase inhibitorsUSC cell linesNeu gene amplificationEndometrial cancerIrreversible pan-ErbB receptor tyrosine kinase inhibitorEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsEpidermal growth factor receptor 2Cell linesKinase inhibitorsEffect of dacomitinibStandard salvage chemotherapyGrowth factor receptor 2Serous endometrial cancerFlow cytometry-based assayHER2/neuFactor receptor 2Dose-dependent declineGene amplificationCell cycle distributionCytometry-based assayGrowth inhibitionTargeted therapy in the treatment of uterine serous carcinoma
Schwab CL, Santin AD. Targeted therapy in the treatment of uterine serous carcinoma. Pharmacogenomics 2015, 16: 97-99. PMID: 25616096, DOI: 10.2217/pgs.14.176.Peer-Reviewed Original Research
2014
Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo
Lopez S, Schwab CL, Cocco E, Bellone S, Bonazzoli E, English DP, Schwartz PE, Rutherford T, Angioli R, Santin AD. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecologic Oncology 2014, 135: 312-317. PMID: 25172762, PMCID: PMC4270135, DOI: 10.1016/j.ygyno.2014.08.024.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnimalsAntineoplastic AgentsCarcinomaCell Cycle CheckpointsCell Line, TumorCell ProliferationClass I Phosphatidylinositol 3-KinasesDrug Screening Assays, AntitumorFemaleGene AmplificationHumansImidazolesIn Situ Hybridization, FluorescenceIn Vitro TechniquesMiceMiddle AgedNeoplasms, Cystic, Mucinous, and SerousOxazepinesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2Uterine NeoplasmsXenograft Model Antitumor AssaysConceptsHER2/neu gene amplificationUterine serous carcinomaUSC cell linesNeu gene amplificationCell linesHER2/neuPIK3CA mutationsGene amplificationPhosphorylation of S6Serous carcinomaPIK3CA wild typeG0/G1 phaseSelective inhibitorOncogenic PIK3CA mutationsS6 proteinCell cycle distributionPrimary uterine serous carcinomaWild typeDownstream signalingPrimary USC cell linesCell cycleNovel therapeutic optionsDose-dependent increaseDifferential growth inhibitionG1 phaseT‐DM1, a novel antibody–drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo
English DP, Bellone S, Schwab CL, Bortolomai I, Bonazzoli E, Cocco E, Buza N, Hui P, Lopez S, Ratner E, Silasi D, Azodi M, Schwartz PE, Rutherford TJ, Santin AD. T‐DM1, a novel antibody–drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo. Cancer Medicine 2014, 3: 1256-1265. PMID: 24890382, PMCID: PMC4302675, DOI: 10.1002/cam4.274.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAgedAged, 80 and overAnimalsAntibodies, Monoclonal, HumanizedAntibody-Dependent Cell CytotoxicityAntineoplastic AgentsApoptosisCarcinomaCell Cycle CheckpointsCell ProliferationDisease Models, AnimalFemaleGene AmplificationGene ExpressionGene Expression Regulation, NeoplasticHumansImmunohistochemistryIn Situ Hybridization, FluorescenceMaytansineMiddle AgedReceptor, ErbB-2RNA, MessengerTrastuzumabUterine NeoplasmsXenograft Model Antitumor AssaysConceptsUterine serous carcinomaUSC cell linesNovel antibody-drug conjugateT-DM1USC xenograftsAntibody-drug conjugatesSerous carcinomaAntibody-dependent cell-mediated cytotoxicityEpidermal growth factor receptor 2Cell linesPrimary USC cell linesGrowth factor receptor 2Cell-mediated cytotoxicityChromium release assaysNovel treatment optionsHER2 protein overexpressionFactor receptor 2HER2 gene amplificationHER2 protein expressionC-erbB2 gene amplificationGene amplificationDisease refractoryPrimary HER2USC cellsUSC patients
2013
HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor
English DP, Roque DM, Carrara L, Lopez S, Bellone S, Cocco E, Bortolomai I, Schwartz PE, Rutherford T, Santin AD. HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecologic Oncology 2013, 131: 753-758. PMID: 24012800, DOI: 10.1016/j.ygyno.2013.08.033.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsCarcinoma, PapillaryCell Line, TumorCystadenocarcinoma, SerousFemaleGene AmplificationHumansMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MorpholinesMultiprotein ComplexesProtein Kinase InhibitorsReceptor, ErbB-2TOR Serine-Threonine KinasesUterine NeoplasmsConceptsUSC cell linesC-erbB2 gene amplificationUterine serous carcinoma cell linesDual mTORC1/2 inhibitorCarcinoma cell linesC-erbB2Cell linesGene amplificationMTORC1/2 inhibitorsPrimary USC cell linesHER2/neu gene amplificationG0/G1 cell cycle phaseDose-dependent increaseHigh HER-2HER2/neuNeu gene amplificationDose-dependent declinePercentage of cellsUSC patientsHER-2Cell cycle profileDifferential growth inhibitionG1 cell cycle phasePS6 levelsTherapeutic agentsOncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2)
English DP, Bellone S, Cocco E, Bortolomai I, Pecorelli S, Lopez S, Silasi DA, Schwartz PE, Rutherford T, Santin AD. Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2). American Journal Of Obstetrics And Gynecology 2013, 209: 465.e1-465.e9. PMID: 23891627, DOI: 10.1016/j.ajog.2013.07.020.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsBridged Bicyclo Compounds, HeterocyclicCarcinoma, PapillaryCell Line, TumorClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmEndometrial NeoplasmsFemaleGene AmplificationGenes, erbB-2HumansIn Situ Hybridization, FluorescenceMiddle AgedMutationPhosphatidylinositol 3-KinasesPyrimidinesTOR Serine-Threonine KinasesConceptsClass I PI3-kinasePI3-kinaseC-erbB2 gene amplificationOncogenic PIK3CA mutationsMTOR kinaseCell linesGene amplificationUterine serous carcinoma cell linesDownstream cellular responsesCarcinoma cell linesUSC cell linesGene mutationsCellular responsesKinaseDifferential growth inhibitionDNA sequencingDirect DNA sequencingMutationsSitu hybridizationUse of GDCGrowth inhibitionExon 9HER2/neu gene amplificationFishPrimary USC cell linesToward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice
Buza N, English DP, Santin AD, Hui P. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Modern Pathology 2013, 26: 1605-1612. PMID: 23765245, DOI: 10.1038/modpathol.2013.113.Peer-Reviewed Original ResearchConceptsEndometrial serous carcinomaSerous carcinomaHER2 overexpressionEndometrial carcinomaMedical recordsImmunohistochemical scoreHER2 testingProtein expressionHER2 immunohistochemistrySignificant heterogeneityScoring systemMultiple tumor sectionsPure serous carcinomaHER2-positive casesHER2-positive tumorsScoring criteriaEndometrial carcinoma casesFDA criteriaPatients' medical recordsLarge academic centerHER2 FISH resultsHER2 protein overexpressionPromising therapeutic targetOverall concordance rateHER2 immunohistochemical scores
2005
Amplification of c‐erbB2 oncogene
Santin AD, Bellone S, Van Stedum S, Bushen W, Palmieri M, Siegel ER, De Las Casas LE, Roman JJ, Burnett A, Pecorelli S. Amplification of c‐erbB2 oncogene. Cancer 2005, 104: 1391-1397. PMID: 16116605, DOI: 10.1002/cncr.21308.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAgedBiomarkers, TumorBiopsy, NeedleCystadenocarcinoma, PapillaryFemaleGene AmplificationGene Expression Regulation, NeoplasticGenes, erbB-2HumansImmunohistochemistryIn Situ Hybridization, FluorescenceMiddle AgedProbabilityPrognosisReceptor, ErbB-2Risk AssessmentSampling StudiesSensitivity and SpecificityStatistics, NonparametricSurvival AnalysisUterine NeoplasmsConceptsNeu gene amplificationHER-2/neu geneEndometrial carcinomaGene amplificationSerous papillary endometrial carcinomaTumor cellsHER-2/neuNeu genePapillary endometrial carcinomaKaplan-Meier curvesImportant prognostic indicatorAfrican American patientsDisease-related deathLog-rank testShorter survival timeFISH-negative patientsNovel treatment strategiesC patientsSame tumor samplesAggressive variantPatient survivalPoor outcomePoor prognosisPrognostic indicatorClinical managementDetermination of HER2/neu status in uterine serous papillary carcinoma: Comparative analysis of immunohistochemistry and fluorescence in situ hybridization
Santin AD, Bellone S, Van Stedum S, Bushen W, De Las Casas LE, Korourian S, Tian E, Roman JJ, Burnett A, Pecorelli S. Determination of HER2/neu status in uterine serous papillary carcinoma: Comparative analysis of immunohistochemistry and fluorescence in situ hybridization. Gynecologic Oncology 2005, 98: 24-30. PMID: 15894362, DOI: 10.1016/j.ygyno.2005.03.041.Peer-Reviewed Original Research