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 cancerEfficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.
Santin A, Corr B, Spira A, Willmott L, Butrynski J, Tse K, Patel J, Mekan S, Wu T, Lin K, Kuo P, Dumbrava E. Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer. Journal Of Clinical Oncology 2024, jco2302767. PMID: 39083724, DOI: 10.1200/jco.23.02767.Peer-Reviewed Original ResearchProgression-free survivalDuration of responseTreatment-related adverse eventsAdvanced endometrial cancerEndometrial cancerSacituzumab govitecanTrop-2Investigator assessmentSolid tumorsTrophoblast cell surface antigen 2Median duration of responsePhase II basket studyMedian progression-free survivalEnd pointsBaseline tumor specimensClinical benefit ratePlatinum-based therapyStudy drug discontinuationAdvanced solid tumorsMedian follow-upMetastatic solid tumorsTrop-2 expressionSecondary end pointsPrimary end pointEfficacy of SGSacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer
Greenman M, Bellone S, Demirkiran C, Hartwich T, Santin A. Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer. Gynecologic Oncology Reports 2024, 54: 101459. PMID: 39108617, PMCID: PMC11300917, DOI: 10.1016/j.gore.2024.101459.Peer-Reviewed Original ResearchHigh grade serous ovarian cancerAntibody-drug conjugatesSerous ovarian cancerSacituzumab govitecanOvarian cancerTreatment optionsPlatinum-resistant ovarian cancer patientsDose-limiting toxicityOvarian cancer patientsNovel treatment optionsPartial responseRecurrent diseaseDose reductionCancer patientsClinical trialsBackground treatmentTargeted treatmentChemotherapyTreatmentCancerDoseDiseaseOptionsTrop2PatientsPreclinical 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, 1-11. 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 cancerRandomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer (NCT03093155): Updated survival and subgroup analyses
Roque D, Siegel E, Buza N, Bellone S, Huang G, Altwerger G, Andikyan V, Clark M, Azodi M, Schwartz P, Rao G, Ratner E, Santin A. Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer (NCT03093155): Updated survival and subgroup analyses. BJC Reports 2024, 2: 43. DOI: 10.1038/s44276-024-00067-5.Peer-Reviewed Original ResearchPre-treated ovarian cancerOverall survivalBev armsDose reductionOvarian cancerTaxane responseRandomized phase 2 trialRandomized phase II trialPaclitaxel-resistant diseaseResultsThirty-seven patientsTreated with paclitaxelPhase 2 trialBiweekly bevacizumabDays 1,8,15Taxane-sensitiveUpdate survivalProgression-freePeritoneal cancerDose modificationTaxane sensitivityPlatinum resistanceSubset analysisSubgroup analysisResponse ratePatientsTargetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations.
Manrai P, McHenry A, Sun T, Santin A, Ratner E, Lin D, Elvin J, Hui P, Buza N. Targetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations. International Journal Of Gynecological Pathology 2024 PMID: 38914011, DOI: 10.1097/pgp.0000000000001050.Peer-Reviewed Original ResearchEndometrial carcinomaGynecologic malignanciesTyrosine kinase domainHER2-mutated non-small cell lung cancerTargeted anti-HER2 therapyNon-small cell lung cancerHigh-grade endometrioid adenocarcinomasFam-trastuzumab deruxtecanOvarian mucinous adenocarcinomaAnti-HER2 therapyAnti-HER2 drugsHER2 3+US Food and Drug AdministrationCell lung cancerEndometrial serous carcinomaSolid tumor typesStandard treatment recommendationsFood and Drug AdministrationFluorescence in situ hybridizationGynecological cancer typesEndometrial primaryMullerian originSerous carcinomaHER2 IHCEndometrioid adenocarcinomaPhase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).
Erickson B, Enserro D, Lankes H, Dockery L, ghamande S, Oliver M, Gressel G, Castellano T, Ratner E, Deery A, Bishop E, Bradford L, Thomes Pepin J, Burton E, Blank S, Santin A, Havrilesky L, Aghajanian C, Nickles Fader A, Powell M. Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026). Journal Of Clinical Oncology 2024, 42: tps5641-tps5641. DOI: 10.1200/jco.2024.42.16_suppl.tps5641.Peer-Reviewed Original ResearchUterine serous carcinomaSerous carcinomaMaintenance trastuzumabDual anti-HER2 therapyRecurrent uterine serous carcinomaCombination of pertuzumabAnti-HER2 therapyEfficacy of trastuzumabPhase II portionPhase II/III studiesPhase III studyNext generation sequencing testsEndometrial serous carcinomaFixed dose combinationInterstitial lung diseasePhase II resultsPhase II componentSevere heart diseasePhase II dataVaginal brachytherapyUterine carcinosarcomaPartial responseMaintenance therapyIII studiesOverexpress HER2Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy
Danziger M, Noble H, Roque D, Xu F, Rao G, Santin A. Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy. Advances In Experimental Medicine And Biology 2024, 1452: 1-19. PMID: 38805122, DOI: 10.1007/978-3-031-58311-7_1.Peer-Reviewed Original ResearchConceptsOvarian cancer therapyCancer therapyTargets of anti-cancer therapyIntracellular traffickingCellular processesCellular cytoskeletonMicrotubule-active agentsAnti-cancer therapyMicrotubule-stabilizing agentEffective regimenDynamic polymersDevelopment of resistanceB-tubulinTherapeutic challengeMicrotubulesRecurrent settingTherapyEukaryotesCytoskeletonMitosisHeterodimerMotilityTraffickingRegimensReplicationEntering the golden age for antibody-drug conjugates in gynecologic cancer
Greenman M, McNamara B, Mutlu L, Santin A. Entering the golden age for antibody-drug conjugates in gynecologic cancer. Oncoscience 2024, 11: 51-52. PMID: 38770444, PMCID: PMC11104406, DOI: 10.18632/oncoscience.604.Peer-Reviewed Original ResearchPreclinical 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 activityIntegrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix
Bellone S, Jeong K, Halle M, Krakstad C, McNamara B, Greenman M, Mutlu L, Demirkiran C, Hartwich T, Yang-Hartwich Y, Zipponi M, Buza N, Hui P, Raspagliesi F, Lopez S, Paolini B, Milione M, Perrone E, Scambia G, Altwerger G, Ravaggi A, Bignotti E, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Quick C, Angioli R, Terranova C, Zaidi S, Nandi S, Alexandrov L, Siegel E, Choi J, Schlessinger J, Santin A. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2321898121. PMID: 38625939, PMCID: PMC11046577, DOI: 10.1073/pnas.2321898121.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingPatient-derived-xenograftsBase excision repairCopy number lossMultiregion whole-exome sequencingCopy number gainHigh-grade neuroendocrine carcinomaCNV analysisPhylogenetic analysisEvolutionary historyNeuroendocrine cervical cancerHuman papillomavirus DNAMutator phenotypeSensitivity to afatinibGenetic landscapeRecurrent mutationsRNA sequencingGene fusionsMutational landscape analysisExcision repairGenesMutationsPan-HERConsistent with deficiencyNeuroendocrine carcinomaRandomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147)
Sheth S, Oh J, Bellone S, Siegel E, Greenman M, Mutlu L, McNamara B, Pathy S, Clark M, Azodi M, Altwerger G, Andikyan V, Huang G, Ratner E, Kim D, Iwasaki A, Levi A, Buza N, Hui P, Flaherty S, Schwartz P, Santin A. Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147). Clinical Cancer Research 2024, 30: of1-of10. PMID: 38592381, DOI: 10.1158/1078-0432.ccr-23-3639.Peer-Reviewed Original ResearchConceptsRandomized phase II trialCD4/CD8 T cellsT cellsHPV clearanceArm BNo significant differenceClinical surveillanceRate of HPV clearanceSecondary outcomesPre-neoplastic cervical lesionsCervical intraepithelial neoplasiaT cell infiltrationT cell responsesSignificant differenceCIN3 patientsIntraepithelial neoplasiaArm ACervical lesionsImiquimod groupSurveillance armVaginal suppositoriesProspective trialsArm CHPV vaccinationImiquimodPreclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer
McNamara B, Demirkiran C, Hartwich T, Bellone S, Manavella D, Mutlu L, Greenman M, Zipponi M, Yang-Hartwich Y, Yang K, Ratner E, Schwartz P, Coma S, Pachter J, Santin A. Preclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer. Gynecologic Oncology 2024, 183: 133-140. PMID: 38493021, DOI: 10.1016/j.ygyno.2024.01.028.Peer-Reviewed Original ResearchLow grade serous ovarian carcinomaWhole-exome-sequencingGain-of-function mutationsVS-4718Preclinical efficacyLow grade serous ovarian cancerSerous ovarian cancerControl-treated miceTumor growth inhibitionWild-type KRASLoss of heterozygosityDecreased p-ERKRAF/MEK inhibitionMedian survivalOvarian cancerRecurrence rateTherapeutic optionsOral gavageTumor growthTumor samplesIn vivo activityMAPK pathway genesRAF/MEK inhibitorsP-ERKEx vivo360 Health-related quality of life in patients with FRα positive platinum-resistant ovarian cancer treated with mirvetuximab soravtansine vs. investigator’s choice chemotherapy: analysis from the phase 3 MIRASOL trial
Garcia Y, Gorp T, Konecny G, Leary A, Santin A, Crusz S, Mantia-Smaldone G, Lorusso D, Colombo N, Thomes-Pepin J, Roszak A, Ottevanger P, Beiner M, Cibula D, Leath C, Li L, Method M, Moore K. 360 Health-related quality of life in patients with FRα positive platinum-resistant ovarian cancer treated with mirvetuximab soravtansine vs. investigator’s choice chemotherapy: analysis from the phase 3 MIRASOL trial. 2024, a34-a35. DOI: 10.1136/ijgc-2024-esgo.43.Peer-Reviewed Original ResearchCorrection: Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer
Roque D, Siegel E, Buza N, Bellone S, Silasi D, Huang G, Andikyan V, Clark M, Azodi M, Schwartz P, Rao G, Reader J, Hui P, Tymon-Rosario J, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Ratner E, Santin A. Correction: Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer. British Journal Of Cancer 2024, 130: 1073-1073. PMID: 38438590, PMCID: PMC10951353, DOI: 10.1038/s41416-024-02628-4.Peer-Reviewed Original ResearchTargeting cervical cancer with anti-PD-1 antibodies: what is new?
Greenman M, McNamara B, Mutlu L, Santin A. Targeting cervical cancer with anti-PD-1 antibodies: what is new? Expert Opinion On Biological Therapy 2024, 24: 111-114. PMID: 38391293, DOI: 10.1080/14712598.2024.2323596.Peer-Reviewed Original ResearchIncreased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID
Bellone S, Siegel E, Scheim D, Santin A. Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID. Gynecologic Oncology Reports 2024, 51: 101324. PMID: 38273933, PMCID: PMC10809113, DOI: 10.1016/j.gore.2024.101324.Peer-Reviewed Original ResearchElevated von Willebrand factorFactor VIII levelsVon Willebrand factorLong COVIDGynecologic patientsVIII levelsControl patientsD-dimerPlasma levelsFactor VIIID-dimer levelsPost-acute sequelaeLong COVID symptomsFactor VIII plasma levelsMicrovascular damageMicrovascular inflammationRed blood cellsThrombotic complicationsAcute infectionLC patientsPersistent inflammationPathophysiological mechanismsCancer patientsCOVID symptomsPatients
2023
Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19
Scheim D, Vottero P, Santin A, Hirsh A. Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19. International Journal Of Molecular Sciences 2023, 24: 17039. PMID: 38069362, PMCID: PMC10871123, DOI: 10.3390/ijms242317039.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 spike proteinRed blood cellsCOVID-19Severe COVID-19 patientsSpike proteinSevere COVID-19COVID-19 correlatesCOVID-19 patientsCommon cold infectionsCOVID-19 morbidityLong-COVID patientsFuture therapeutic strategiesSARS-CoV-2Key risk factorsKey morbiditiesSurface of plateletsSevere morbidityClinical efficacyVascular damageViral loadMicrovascular occlusionRisk factorsCOVID patientsClinical studiesClinical susceptibilityIncreased serum 1,25-dihydroxyvitamin D levels in gynecologic cancer patients with Post-Acute-Covid-Sequela (PASC)/Long COVID
Bellone S, Siegel E, Santin A. Increased serum 1,25-dihydroxyvitamin D levels in gynecologic cancer patients with Post-Acute-Covid-Sequela (PASC)/Long COVID. Gynecologic Oncology Reports 2023, 50: 101301. PMID: 38029227, PMCID: PMC10654147, DOI: 10.1016/j.gore.2023.101301.Peer-Reviewed Original ResearchGynecologic cancer patientsLong COVIDCancer patientsVitamin DPotent anti-inflammatory activityDihydroxyvitamin D levelsPost-acute sequelaeLong COVID symptomsAnti-inflammatory activityMental health impairmentControl cancer patientsExtrarenal conversionPost-AcuteControl patientsAcute infectionBone healthLC patientsPersistent inflammationD levelsCOVID symptomsImmune cellsPlasmatic levelsNovel biomarkersPatientsAbnormal levels