2024
Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting
Prosz A, Sahgal P, Huffman B, Sztupinszki Z, Morris C, Chen D, Börcsök J, Diossy M, Tisza V, Spisak S, Likasitwatanakul P, Rusz O, Csabai I, Cecchini M, Baca Y, Elliott A, Enzinger P, Singh H, Ubellaker J, Lazaro J, Cleary J, Szallasi Z, Sethi N. Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting. Npj Precision Oncology 2024, 8: 87. PMID: 38589664, PMCID: PMC11001913, DOI: 10.1038/s41698-024-00561-6.Peer-Reviewed Original ResearchNucleotide excision repairGastric cancer cell linesNucleotide excision repair-deficientPlatinum chemotherapyHR deficiencyCancer cell linesPARP inhibitorsHomologous recombinationGenome sequence dataSensitivity to platinum chemotherapySingle-cell RNA sequencingCell linesHR-deficient cancersDNA repair pathwaysSensitivity to cisplatinRad51 foci assaysMutational signature analysisSequence dataGenomic featuresWhole exomeInduce apoptosisRNA sequencingGastroesophageal adenocarcinomaRepair pathwaysHRD scoreEGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling
Hu Z, Chen P, Li W, Krone M, Zheng S, Saarbach J, Velasco I, Hines J, Liu Y, Crews C. EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling. Science Advances 2024, 10: eadj7251. PMID: 38536914, PMCID: PMC10971414, DOI: 10.1126/sciadv.adj7251.Peer-Reviewed Original ResearchConceptsInhibit cancer cell viabilityProteome-wide levelCancer cell viabilityDifferential signaling pathwaysPhosphoproteomic approachTyrosine dephosphorylationProtein dephosphorylationSignal transductionActivating dephosphorylationInduce apoptosisReceptor tyrosine kinase inhibitorsRTK activationSignaling pathwayInhibition of kinasesDephosphorylationEpidermal growth factor receptorGrowth factor receptorCell viabilityFactor receptorInhibitory approachesTyrosineTyrosine kinase inhibitorsInhibitory effectInhibitory potentialKinase inhibitorsA synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress
Fedeles B, Bhardwaj R, Ishikawa Y, Khumsubdee S, Krappitz M, Gubina N, Volpe I, Andrade D, Westergerling P, Staudner T, Campolo J, Liu S, Dong K, Cai Y, Rehman M, Gallagher A, Ruchirawat S, Croy R, Essigmann J, Fedeles S, Somlo S. A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2317344121. PMID: 38241440, PMCID: PMC10823221, DOI: 10.1073/pnas.2317344121.Peer-Reviewed Original ResearchConceptsCyst cellsAutosomal dominant polycystic kidney diseaseMouse models of autosomal dominant polycystic kidney diseasePolycystic kidney diseaseModel of autosomal dominant polycystic kidney diseaseKidney diseaseDeveloped primersMitochondrial oxidative stressPathophysiology of autosomal dominant polycystic kidney diseaseOxidative stressInduce apoptosisMitochondrial respirationCystic cellsUp-regulating aerobic glycolysisHomozygous inactivationMonogenic causeDominant polycystic kidney diseaseAerobic glycolysisRenal replacement therapyApoptosisEnd-stage kidney diseaseAnti-tumor agentsAdult mouse modelChronic kidney diseaseAlkylate DNA
2019
Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors
Timme N, Han Y, Liu S, Yosief H, García H, Bei Y, Klironomos F, MacArthur I, Szymansky A, von Stebut J, Bardinet V, Dohna C, Künkele A, Rolff J, Hundsdörfer P, Lissat A, Seifert G, Eggert A, Schulte J, Zhang W, Henssen A. Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors. Translational Oncology 2019, 13: 221-232. PMID: 31869746, PMCID: PMC6931204, DOI: 10.1016/j.tranon.2019.09.013.Peer-Reviewed Original ResearchPediatric tumor cell linesTumor cell linesTreatment of patient-derived xenograftsClinical response to therapySignificant tumor regressionPediatric solid tumorsResponse to therapyPatient-derived xenograftsPediatric cancer modelsTumor-specific activationCell linesRhabdomyosarcoma tumor cellsTumor regressionPreclinical modelsSolid tumorsAntitumor effectCancer modelsTumor cellsConcurrent inhibitionAntitumor activityInduce apoptosisSimultaneous inhibitionMolecular targetsBRD4 inhibitorsCentral regulator
2015
Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration
Xiang W, Cheong J, Ang S, Teo B, Xu P, Asari K, Sun W, Than H, Bunte R, Virshup D, Chuah C. Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration. Oncotarget 2015, 6: 33769-33780. PMID: 26378050, PMCID: PMC4741801, DOI: 10.18632/oncotarget.5615.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsAntigens, CD34Antineoplastic Combined Chemotherapy ProtocolsApoptosisbeta CateninBlast CrisisCasein Kinase ICell Line, TumorCell ProliferationDasatinibHumansInhibitory Concentration 50K562 CellsLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMiceMice, SCIDMitochondriaNeoplasm TransplantationPhosphorylationPyrvinium CompoundsRNA InterferenceConceptsChronic phase chronic myeloid leukemiaTyrosine kinase inhibitorsBCR-ABL1 tyrosine kinase inhibitorsMitochondrial respirationInduce apoptosisBP-CMLBlast phaseFDA-approved anthelminthic drugBCR-ABL1Casein kinase 1aMyeloid leukemiaEffects of pyrviniumTargeting mitochondrial respirationInhibition of mitochondrial respirationCD34+ progenitor cellsInhibit mitochondrial respirationBP-CML patientsCD34+ cellsChronic myeloid leukemiaCord blood CD34Inhibited tumor growthSelf-renewal capacityWnt/b-catenin signaling pathwayInhibited colony formationKinase 1A
2014
Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy
Pandey A, Kulkarni A, Roy B, Goldman A, Sarangi S, Sengupta P, Phipps C, Kopparam J, Oh M, Basu S, Kohandel M, Sengupta S. Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy. Cancer Research 2014, 74: 675-685. PMID: 24121494, PMCID: PMC3946433, DOI: 10.1158/0008-5472.can-12-3783.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorCell SurvivalCisplatinErbB ReceptorsFemaleHumansMiceModels, BiologicalNanoparticlesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktReproducibility of ResultsSignal TransductionConceptsMolecular targeted therapeuticsEnhanced antitumor efficacyAntitumor efficacyBreast cancerCytotoxic agents to tumorsPharmacological inhibitor of PI3KImpact of drug sequencingCombination of nanomedicineAgents to tumorsBreast cancer cellsPI3K) pathwayManagement of cancerInhibitor of PI3KCytotoxic nanoparticlesCombination therapyDrug sequenceOncogenic driversAntitumor outcomesProsurvival signalingCancer cellsPharmacological inhibitorsCancer chemotherapyInduce apoptosisCancerIn vivo validation
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