2024
Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer
Hartwich T, Mansolf M, Demirkiran C, Greenman M, Bellone S, McNamara B, Nandi S, Alexandrov L, Yang‐Hartwich Y, Coma S, Pachter J, Santin A. Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer. Cancer Medicine 2024, 13: e70210. PMID: 39240189, PMCID: PMC11378359, DOI: 10.1002/cam4.70210.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzamidesCarcinoma, EndometrioidCell Line, TumorCell ProliferationEndometrial NeoplasmsExome SequencingFemaleFocal Adhesion Kinase 1HumansImidazolesMiceNeoplasm GradingOxazepinesProtein Kinase InhibitorsPyrazinesSulfonamidesXenograft Model Antitumor AssaysConceptsFocal adhesion kinaseWhole-exome sequencingEndometrial cancer cell linesVS-4718Cell linesRas/MAPK pathwayPhosphorylated focal adhesion kinaseWestern blot assayWhole-exome sequencing resultsRAF/MEK inhibitionEAC cell linesBlot assayP-FAKGenetic landscapeCell cycleEndometrial cancerGenetic derangementsDefactinibP-MEKGrowth inhibitionRAF/MEKRas/MAPKCell viabilityP-ERKHigh-grade endometrial cancer
2020
Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial
Oaknin A, Friedman CF, Roman LD, D’Souza A, Brana I, Bidard F, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, T.M. K, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, Monk BJ. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecologic Oncology 2020, 159: 150-156. PMID: 32723675, PMCID: PMC8336424, DOI: 10.1016/j.ygyno.2020.07.025.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultDiarrheaFemaleHumansKaplan-Meier EstimateMiddle AgedMutationNauseaNeoplasm Recurrence, LocalProgression-Free SurvivalProtein Kinase InhibitorsQuinolinesReceptor, ErbB-2Response Evaluation Criteria in Solid TumorsSeverity of Illness IndexUterine Cervical NeoplasmsConceptsProgression-free survivalClinical benefit rateObjective response rateCervical cancerOverall survivalHER2 mutationsBasket trialsMetastatic/recurrent cervical cancerAdvanced/recurrent diseaseMedian progression-free survivalCommon HER2 mutationsGrade 3 diarrheaGrade 4 eventsHER2-mutant cancersSafety of neratinibCommon adverse eventsMedian overall survivalRecurrent cervical cancerMetastatic cervical cancerNew safety signalsPhase II basket trialPlatinum-based treatmentTyrosine kinase inhibitorsWarrants further investigationEligible patients
2019
PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers
Bonazzoli E, Cocco E, Lopez S, Bellone S, Zammataro L, Bianchi A, Manzano A, Yadav G, Manara P, Perrone E, Haines K, Espinal M, Dugan K, Menderes G, Altwerger G, Han C, Zeybek B, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Santin AD. PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers. Gynecologic Oncology 2019, 153: 158-164. PMID: 30630630, PMCID: PMC6430698, DOI: 10.1016/j.ygyno.2019.01.002.Peer-Reviewed Original ResearchMeSH KeywordsAdultAfatinibAgedAnimalsAntineoplastic AgentsCell Line, TumorClass I Phosphatidylinositol 3-KinasesClass Ia Phosphatidylinositol 3-KinaseDrug Resistance, NeoplasmFemaleGenital Neoplasms, FemaleHumansMiceMice, SCIDMiddle AgedMutationPhosphatidylinositol 3-KinasesProtein Kinase InhibitorsReceptor, ErbB-2TransfectionXenograft Model Antitumor AssaysConceptsHER2/neuAKT/mTOR pathwayPIK3CA mutationsMTOR pathwayActivity of afatinibEffect of afatinibPI3K/AKT/mTOR pathwayPotential mechanismsPIK3CA/AKT/mTOR pathwayRapid tumor growthGreater compensatory increasePI3K mutationsAmplification/mutationOncogenic PIK3CA mutationsAfatinib exposurePIK3CA H1047RGynecological cancerClinical trialsMTOR inhibitorsAfatinibTumor growthCompensatory increasePhosphorylated Akt proteinPIK3CA geneC-erb
2016
Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer.
Menderes G, Clark M, Santin AD. Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer. Discovery Medicine 2016, 21: 293-303. PMID: 27232515.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntineoplastic AgentsClass I Phosphatidylinositol 3-KinasesCyclin ECystadenocarcinoma, SerousEndometrial NeoplasmsEpothilonesExomeFemaleHumansMolecular Targeted TherapyMutationNeoplasm Recurrence, LocalOncogene ProteinsPrognosisProtein Kinase InhibitorsProtein Phosphatase 2RadioimmunotherapyReceptor, ErbB-2Sequence Analysis, DNASignal TransductionTOR Serine-Threonine KinasesTubulin ModulatorsTumor Suppressor Protein p53Uterine NeoplasmsVascular Endothelial Growth Factor AConceptsUterine serous carcinomaEndometrial cancerSerous carcinomaTreatment of USCPIK3CA/AKT/mTOREndometrial cancer casesRecent whole-exome sequencing studiesHER2/neu geneNovel therapeutic targetAkt/mTORBiologic therapyAggressive variantDismal prognosisAggressive subtypeWhole-exome sequencing studiesCancer casesTherapeutic targetSubsequent deathDriver mutationsNeu geneGain of functionCarcinomaTherapyCancerSequencing studies
2015
Immunotherapy and targeted therapy for cervical cancer: an update
Menderes G, Black J, Schwab CL, Santin AD. Immunotherapy and targeted therapy for cervical cancer: an update. Expert Review Of Anticancer Therapy 2015, 16: 83-98. PMID: 26568261, DOI: 10.1586/14737140.2016.1121108.Peer-Reviewed Original ResearchConceptsCervical cancer patientsCervical cancerCancer patientsImmune check pointsUse of immunotherapyMetastatic cervical cancerPrognosis of patientsActionable driver mutationsTyrosine kinase inhibitorsImmune system interactionsImmunotherapy studiesMedian survivalAngiogenesis inhibitorsChemotherapeutic drugsPatientsDriver mutationsKinase inhibitorsNew therapeuticsCancerNext-generation sequencingImmunotherapyTherapyGeneration sequencingInhibitorsPrognosisNeratinib 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 inhibition
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 agents
2012
EGFR/HER-targeted therapeutics in ovarian cancer
Wilken JA, Badri T, Cross S, Raji R, Santin AD, Schwartz P, Branscum AJ, Baron AT, Sakhitab AI, Maihle NJ. EGFR/HER-targeted therapeutics in ovarian cancer. Future Medicinal Chemistry 2012, 4: 447-469. PMID: 22416774, PMCID: PMC4620931, DOI: 10.4155/fmc.12.11.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerOvarian cancerHuman epidermal growth factor receptor (HER) familyEpidermal growth factor receptor familyGrowth factor receptor familyTreatment modalitiesFactor receptor familyClinical developmentDiverse malignanciesEGFR/Clinical settingUS FDACancerNew drugsReceptor familyPatientsMalignancyTherapeuticsTreatmentTyrosine kinaseSurvivalSame periodCarcinomaMajor roleEtiology