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 cancerPreclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma
McNamara B, Greenman M, Bellone S, Santin L, Demirkiran C, Mutlu L, Hartwich T, Yang-Hartwich Y, Ratner E, Schwartz P, Santin A. Preclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma. Gynecologic Oncology 2024, 189: 16-23. PMID: 38981151, DOI: 10.1016/j.ygyno.2024.07.002.Peer-Reviewed Original ResearchTargets trophoblast cell-surface antigen-2Epithelial ovarian cancerAntibody-dependent cellular cytotoxicityPreclinical activityAntibody drug conjugatesOvarian cancerCell linesTumor cellsTrophoblast cell surface antigen 2Cell line-derived xenograft modelFlow cytometryCompared to tumor cellsEpithelial ovarian cancer cell linesOvarian cancer cell linesTumor cells in vitroOvarian cancer patientsPeripheral-blood lymphocytesEOC cell linesTumor growth suppressionAnnexin V-positiveGynecologic cancer mortalityIn vivo antitumor activityCells in vitroPrimary cell linesUnmet medical needTrastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2
Mutlu L, McNamara B, Bellone S, Manavella D, Demirkiran C, Greenman M, Verzosa M, Buza N, Hui P, Hartwich T, Harold J, Yang-Hartwich Y, Zipponi M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Schwartz P, Santin A. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2. Clinical & Experimental Metastasis 2024, 41: 765-775. PMID: 38909139, DOI: 10.1007/s10585-024-10297-z.Peer-Reviewed Original ResearchHigh-grade serous ovarian cancerClear cell carcinomaHER2-targeting antibody-drug conjugateAntibody-drug conjugatesT-DXdReceptor over-expressionTrastuzumab deruxtecanXenograft modelCell linesOvarian clear cell carcinomaOvarian cancer cell linesTumors overexpressing HER2Biologically aggressive tumorsFluorescence in situ hybridization assaySerous ovarian cancerEffective antibody-drug conjugatesIn vivo antitumor activityMouse xenograft modelMetastatic cell linesDS-8201aCancer cell linesAggressive tumorsHER2 expressionCell carcinomaOvarian cancerPreclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas
Demirkiran C, Greenman M, Bellone S, McNamara B, Hartwich T, Manavella D, Mutlu L, Zipponi M, Yang-Hartwich Y, Yang K, Ratner E, Schwartz P, Coma S, Pachter J, Santin A. Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas. Gynecologic Oncology 2024, 187: 12-20. PMID: 38703673, DOI: 10.1016/j.ygyno.2024.04.010.Peer-Reviewed Original ResearchFocal adhesion kinaseUC cell linesWhole-exome-sequencingFAK inhibitorCell linesFocal adhesion kinase inhibitionPhosphorylated (p)‑FAKWestern blot assayRAF/MEK inhibitionUterine carcinosarcomaRAS/MAPK pathway genesPreclinical in vitroBlot assayVS-4718Cell cycle assayGenetic landscapePathway genesMAP2KGenetic alterationsDecreased p-ERKCycle assaySuperior tumor growth inhibitionBiologically aggressive tumorsGrowth inhibitionIn vitro activity
2023
In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma.
Mutlu L, Manavella D, Bellone S, McNamara B, Harold J, Mauricio D, Siegel E, Buza N, Hui P, Hartwich T, Yang-Hartwich Y, Demirkiran C, Verzosa M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Dottino P, Schwartz P, Santin A. In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma. Molecular Cancer Therapeutics 2023, 22: 1404-1412. PMID: 37676984, DOI: 10.1158/1535-7163.mct-23-0126.Peer-Reviewed Original ResearchConceptsUterine serous carcinomaAntibody-dependent cellular cytotoxicityT-DXdUSC patientsUSC cell linesTrastuzumab deruxtecanSerous carcinomaHER2 expressionClinical trialsRecurrent uterine serous carcinomaTopoisomerase I inhibitor payloadSignificant antibody-dependent cellular cytotoxicityCell linesMultiple tumor indicationsPrimary USC cell linesLow HER2 expressionFuture clinical trialsHigh recurrence ratePeripheral blood lymphocytesERBB2 gene amplificationGrowth suppressionHER2-overexpressing cell linesTumor growth suppressionOverall survivalStandard chemotherapyNRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8
Anandhan A, Dodson M, Shakya A, Chen J, Liu P, Wei Y, Tan H, Wang Q, Jiang Z, Yang K, Garcia J, Chambers S, Chapman E, Ooi A, Yang-Hartwich Y, Stockwell B, Zhang D. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Science Advances 2023, 9: eade9585. PMID: 36724221, PMCID: PMC9891695, DOI: 10.1126/sciadv.ade9585.Peer-Reviewed Original ResearchConceptsLabile iron poolNFE2L2/Human ovarian cancer tissuesCancer cellsOvarian cancer cell linesOvarian cancer tissuesIntracellular labile iron poolIron homeostasisCancer cell linesPreclinical modelsNrf2 inhibitionCancer tissuesNrf2 levelsCancer treatmentFerroptotic deathNrf2Ferroptosis resistanceKnockout cellsCell linesUntapped strategyFerroptosisIron poolCellsHomeostasisExpressionThe Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo
Han C, McNamara B, Bellone S, Harold J, Manara P, Hartwich T, Mutlu L, Yang-Hartwich Y, Zipponi M, Demirkiran C, Verzosa M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Dottino P, Schwartz P, Santin A. The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo. Gynecologic Oncology 2023, 170: 172-178. PMID: 36706643, PMCID: PMC10023457, DOI: 10.1016/j.ygyno.2023.01.015.Peer-Reviewed Original ResearchConceptsCombination of olaparibOvarian cancerHER2 expressionSingle agentCell linesGynecologic cancer mortalityHER2-negative tumorsOvarian cancer cell linesOvarian cancer patientsEpithelial ovarian carcinomaNovel therapeutic optionsOC cell linesUnmet medical needPoly (ADP-ribose) polymerase (PARP) inhibitorsPan-ErbB inhibitorSingle-agent olaparibPolymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPrimary HER2Cancer cell linesNegative tumorsTherapeutic optionsCancer mortalityCancer patientsNeu expressionTrastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression
Mauricio D, Bellone S, Mutlu L, McNamara B, Manavella D, Demirkiran C, Verzosa M, Buza N, Hui P, Hartwich T, Harold J, Yang-Hartwich Y, Zipponi M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Schwartz P, Santin A. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression. Gynecologic Oncology 2023, 170: 38-45. PMID: 36610380, PMCID: PMC10445234, DOI: 10.1016/j.ygyno.2022.12.018.Peer-Reviewed Original ResearchConceptsHER2/neu expressionDS-8201aAntibody-drug conjugatesNeu expressionCS cell linesTrastuzumab deruxtecanOvarian carcinosarcomaTopoisomerase I inhibitor payloadCell linesAggressive gynecologic malignancyLimited therapeutic optionsEffective antibody-drug conjugatesCarcinosarcoma cell lineGynecologic malignanciesTherapeutic optionsIsotype controlSarcomatous elementsXenograft modelBystander killingFlow cytometryTumor cellsCarcinosarcomaAntitumor activityVivo studiesVivo activity
2022
Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor
Manavella D, McNamara B, Harold J, Bellone S, Hartwich T, Yang-Hartwich Y, Mutlu L, Zipponi M, Demirkiran C, Verzosa M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Schwartz P, Dottino P, Choi J, Alexandrov L, Buza N, Hui P, Santin A. Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor. Gynecologic Oncology 2022, 169: 98-105. PMID: 36525930, PMCID: PMC9925406, DOI: 10.1016/j.ygyno.2022.12.003.Peer-Reviewed Original ResearchConceptsHomologous recombination deficiencyCS cell linesCell linesWestern blotKinase inhibitorsOverall animal survivalProtein expressionDose-dependent increaseDose-dependent inhibitionCarcinosarcoma cell lineTumor growth inhibitionCaspase-3 expressionEndometrioid histologyAggressive malignancyUterine carcinosarcomaCS patientsPreclinical activityClinical trialsEpithelial componentAnimal survivalXenograftsApoptosis markersRecombination deficiencyP-ATRP-Chk1Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate [ADP]- ribose) polymerase (PARP) inhibitor
Tymon-Rosario JR, Manara P, Manavella DD, Bellone S, Hartwich TMP, Harold J, Yang-Hartwich Y, Zipponi M, Choi J, Jeong K, Mutlu L, Yang K, Altwerger G, Menderes G, Ratner E, Huang GS, Clark M, Andikyan V, Azodi M, Schwartz PE, Alexandrov LB, Santin AD. Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate [ADP]- ribose) polymerase (PARP) inhibitor. Gynecologic Oncology 2022, 166: 117-125. PMID: 35599167, DOI: 10.1016/j.ygyno.2022.05.005.Peer-Reviewed Original ResearchConceptsUterine carcinosarcomaCS cell linesSignature 3Cell linesPolymerase inhibitorsOverall animal survivalFresh tumor samplesPoly (ADP-ribose) polymerase (PARP) inhibitorsXenograft tumor growthG2/M phaseAggressive malignancyCS patientsPrimary tumorCell cycle arrestPrimary cell linesPoor survivalClinical studiesPreclinical sensitivityCarcinosarcomaTumor growthAnimal survivalOlaparib activityTumor samplesOlaparibAntitumor activity
2020
Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA
Kang M, Tang B, Li J, Zhou Z, Liu K, Wang R, Jiang Z, Bi F, Patrick D, Kim D, Mitra AK, Yang-Hartwich Y. Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA. Molecular Cancer 2020, 19: 143. PMID: 32928232, PMCID: PMC7489042, DOI: 10.1186/s12943-020-01248-9.Peer-Reviewed Original ResearchConceptsNon-coding RNA transcriptsNasopharyngeal carcinomaCancer cell linesP53 transcriptional activationPrognostic markerTumor suppressor functionAmino acid residuesCell linesTumor growthNovel microproteinWild-type p53Cellular functionsMetastatic nasopharyngeal carcinomaTranscriptional activationPotential prognostic markerMitochondrial membraneUnfavorable prognostic markerCervical cancer cell linesRNA transcriptsMitochondrial massTumor suppressorMiR-34a expressionAcid residuesNormal human colonNPC clinical samples
2019
Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription
Chong KY, Kang M, Garofalo F, Ueno D, Liang H, Cady S, Madarikan O, Pitruzzello N, Tsai CH, Hartwich T, Shuch B, Yang-Hartwich Y. Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription. Molecular Pharmacology 2019, 96: 168-179. PMID: 31175180, DOI: 10.1124/mol.119.116137.Peer-Reviewed Original ResearchMeSH KeywordsBenzoquinonesCell Line, TumorDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionFemaleGene Expression Regulation, NeoplasticHSP90 Heat-Shock ProteinsHumansKidney NeoplasmsLactams, MacrocyclicNasopharyngeal NeoplasmsNuclear ProteinsOvarian NeoplasmsPhosphorylationPromoter Regions, GeneticSTAT3 Transcription FactorTissue Array AnalysisTranscription, GeneticTwist-Related Protein 1ConceptsEpithelial-mesenchymal transitionHsp90 inhibitorsTwist1 transcriptionMolecular chaperone heat shock protein 90Chaperone heat shock protein 90Involvement of Hsp90Heat shock protein 90Cancer cell linesRole of Hsp90Binding of STAT3Inhibition of Hsp90Shock protein 90Cell linesProximity ligation assayHsp90 inhibitor 17TWIST1 mRNA expressionTranscription factorsSignal transducerProtein 90Promoter activityTranscription 3New therapeutic opportunitiesHsp90Molecular mechanismsSTAT3 activityProtein kinase Cα–mediated phosphorylation of Twist1 at Ser-144 prevents Twist1 ubiquitination and stabilizes it
Tedja R, Roberts CM, Alvero AB, Cardenas C, Yang-Hartwich Y, Spadinger S, Pitruzzello M, Yin G, Glackin CA, Mor G. Protein kinase Cα–mediated phosphorylation of Twist1 at Ser-144 prevents Twist1 ubiquitination and stabilizes it. Journal Of Biological Chemistry 2019, 294: 5082-5093. PMID: 30733340, PMCID: PMC6442047, DOI: 10.1074/jbc.ra118.005921.Peer-Reviewed Original ResearchConceptsProtein kinase CPhosphorylation sitesHelix transcription factorPhosphorylation of Twist1Candidate phosphorylation sitesProtein kinase CαCombination of immunoblottingUbiquitination eventsTwist1 phosphorylationTranscription factorsEmbryonic developmentKnockout experimentsSer-144CRISPR/Twist1 proteinKinase CInvasive phenotypeAdult cellsPhosphorylationTwist1UbiquitinationCancer developmentCell linesTwist1 expressionPKCα
2014
Detection of p53 Protein Aggregation in Cancer Cell Lines and Tumor Samples
Yang-Hartwich Y, Bingham J, Garofalo F, Alvero AB, Mor G. Detection of p53 Protein Aggregation in Cancer Cell Lines and Tumor Samples. Methods In Molecular Biology 2014, 1219: 75-86. PMID: 25308263, DOI: 10.1007/978-1-4939-1661-0_7.Peer-Reviewed Original ResearchConceptsCancer cell linesPro-apoptotic functionAggregation of p53P53 proteinCancer cellsCell linesP53 aggregationAmyloid-like oligomersProtein aggregationApoptotic signalsInactive conformationTumor samplesFunctional p53ProteinGenetic mutationsTumor progressionCentral roleP53Dysfunctional p53 proteinCellsAggregationMutationsApoptosisDeregulationLines