2017
Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma
Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, Codega P, Nichol D, Clark O, Hsieh WY, Rohle D, Rosenblum M, Viale A, Tabar VS, Brennan CW, Gavrilovic IT, Kaley TJ, Nolan CP, Omuro A, Pentsova E, Thomas AA, Tsyvkin E, Noy A, Palomba ML, Hamlin P, Sauter CS, Moskowitz CH, Wolfe J, Dogan A, Won M, Glass J, Peak S, Lallana EC, Hatzoglou V, Reiner AS, Gutin PH, Huse JT, Panageas KS, Graeber TG, Schultz N, DeAngelis LM, Mellinghoff IK. Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discovery 2017, 7: 1018-1029. PMID: 28619981, PMCID: PMC5581705, DOI: 10.1158/2159-8290.cd-17-0613.Peer-Reviewed Original ResearchMeSH KeywordsAdenineAdultAgammaglobulinaemia Tyrosine KinaseAgedAged, 80 and overAntineoplastic AgentsCARD Signaling Adaptor ProteinsCentral Nervous System NeoplasmsDrug Resistance, NeoplasmFemaleGuanylate CyclaseHumansLymphoma, B-CellMaleMaximum Tolerated DoseMiddle AgedMutationPiperidinesProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrazolesPyrimidinesTreatment OutcomeYoung AdultConceptsPrimary central nervous system lymphomaBruton's tyrosine kinaseB-cell lymphomaRefractory B-cell lymphomaB cell antigen receptorCentral nervous system lymphomaRole of BTKDiffuse large B-cell lymphomaLarge B-cell lymphomaPhase I clinical trialClass BTK inhibitorIncomplete tumor responseNervous system lymphomaToll-like receptorsPI3K/mTORIbrutinib responseCNS lymphomaClinical responseComplete responseReceptor-associated proteinSystem lymphomaActivation markersTumor responseClinical trialsPCNSL cellsA call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.
Yokota T, Bendell J, LoRusso P, Tsushima T, Desai V, Kenmotsu H, Watanabe J, Ono A, Murugesan B, Silva J, Naito T, Greenberg J, Kumar P, Wang Y, Jikoh T, Shiga R, Ho A, Gounder M. A call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan. Journal Of Clinical Oncology 2017, 35: 2536-2536. DOI: 10.1200/jco.2017.35.15_suppl.2536.Peer-Reviewed Original ResearchMaximum-tolerated doseBody mass indexAdvanced solid tumorsBody weightPhase IFrequent treatment-related adverse eventsSolid tumorsNon-small cell lung cancerGrade 3 lung infectionHuman Phase I StudyTreatment-related adverse eventsCorresponding phase IGrade 3 dehydrationGrade 3 fatigueGrade 3 stomatitisGrade 4 hyperglycemiaPhase 2 doseGrade 3 rashCell lung cancerPhase I studiesSquamous cell carcinomaPI3K/mTOR dual inhibitorPI3K/mTORMTOR dual inhibitorStable disease
2016
ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
Muranen T, Selfors L, Hwang J, Gallegos L, Coloff J, Thoreen C, Kang S, Sabatini D, Mills G, Brugge J. ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP. Cancer Research 2016, 76: 7168-7180. PMID: 27913436, PMCID: PMC5161652, DOI: 10.1158/0008-5472.can-16-0155.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsBlotting, WesternCell Line, TumorCell ProliferationDrug Resistance, NeoplasmExtracellular Signal-Regulated MAP KinasesFemaleFluorescent Antibody TechniqueHeterograftsHumansMAP Kinase Signaling SystemMiceMice, Inbred NODMicroscopy, ConfocalNeoplasms, Experimentalp38 Mitogen-Activated Protein KinasesPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsProtein Kinase InhibitorsProto-Oncogene MasProto-Oncogene Proteins c-mycSignal TransductionTOR Serine-Threonine KinasesTranscription FactorsYAP-Signaling ProteinsConceptsPI3K/mTOR inhibitorMTOR inhibitorsTumor cellsPI3K/mTOR pathwayCell-targeted therapiesTranscriptional regulator c-MycPI3K/mTORAnimal tumor modelsUpregulation of MYCChronic inhibitionInhibition of p38Cellular signaling mechanismsTumor growthMTOR pathwayTumor modelAberrant activationTherapyStress kinase p38C-MycKinase p38InhibitionConstitutive ERK activityAttractive targetContext-dependent mechanismsProliferation arrestmTOR Kinase Inhibitors Enhance Efficacy of TKIs in Preclinical Models of Ph-like B-ALL
Gotesman M, Vo T, Mallya S, Zhang Q, Shi C, Müschen M, Weinstock D, Mullighan C, Tasian S, Konopleva M, Fruman D. mTOR Kinase Inhibitors Enhance Efficacy of TKIs in Preclinical Models of Ph-like B-ALL. Blood 2016, 128: 2763. DOI: 10.1182/blood.v128.22.2763.2763.Peer-Reviewed Original ResearchEvent-free survivalTOR-KIsPDX modelsBone marrowInhibitor monotherapyInhibitor therapyMurine bone marrowPatient-derived xenograft modelsTyrosine kinase inhibitor imatinibCompelling preclinical rationaleRearrangements of CRLF2Daily oral gavageEnd of treatmentKinase inhibitor therapyPrior preclinical studiesKinase inhibitor imatinibPI3K/mTORMouse bone marrow cellsBone marrow cellsNormal mouse bone marrow cellsReata PharmaceuticalsTKI dasatinibMost patientsLeukemia burdenPreclinical rationale
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