2023
Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies
Cosgun K, Robinson M, Oulghazi S, Xu L, Xiao G, Chan L, Lee J, Kume K, Leveille E, Arce D, Khanduja D, Feldhahn N, Song J, Chan W, Chen J, Taketo M, Schjerven H, Jellusova J, Kothari S, Davids M, Müschen M. Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies. Blood 2023, 142: 2818. DOI: 10.1182/blood-2023-190522.Peer-Reviewed Original ResearchFavorable safety profileSmall molecule inhibitorsT-lymphoid malignancyΒ-catenin degradationLymphoid malignanciesΒ-cateninInteractome studiesSafety profileClinical trialsMolecule inhibitorsLow nanomolar concentrationsΒ-catenin accumulationSolid tumorsRefractory B-cell malignanciesCell deathPK/PD profilesZinc finger proteinRefractory lymphoid malignanciesChIP-seq analysisPhase 2 trialMYC target genesT-cell lymphomaColony formationRapid nuclear accumulationWnt/β-catenin pathway
2018
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Sullivan-Reed K, Bolton-Gillespie E, Dasgupta Y, Langer S, Siciliano M, Nieborowska-Skorska M, Hanamshet K, Belyaeva EA, Bernhardy AJ, Lee J, Moore M, Zhao H, Valent P, Matlawska-Wasowska K, Müschen M, Bhatia S, Bhatia R, Johnson N, Wasik MA, Mazin AV, Skorski T. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells. Cell Reports 2018, 23: 3127-3136. PMID: 29898385, PMCID: PMC6082171, DOI: 10.1016/j.celrep.2018.05.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBRCA1 ProteinBRCA2 ProteinDNA RepairFemaleFusion Proteins, bcr-ablHomologous RecombinationHumansImatinib MesylateKaplan-Meier EstimateLeukemia, Myeloid, AcuteMaleMiceMice, Inbred NODMice, KnockoutPhthalazinesPiperazinesPoly (ADP-Ribose) Polymerase-1Rad52 DNA Repair and Recombination ProteinSynthetic Lethal MutationsTumor Suppressor p53-Binding Protein 1ConceptsTumor cellsBRCA-deficient tumor cellsSimultaneous targetingBRCA-deficient tumorsClinical trialsProlonged latencyImmunodeficient miceTherapeutic outcomesBRCA1-deficient tumorsPARP inhibitorsBRCA-deficient cellsMinimal toxicitySynergistic activitySynthetic lethal effectTumorsNormal cellsPARPiSynthetic lethalityInhibitorsLethal effectsCellsDominant negative mutantSynergistic accumulationMalignancyTargeting
2015
Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell 2015, 27: 409-425. PMID: 25759025, PMCID: PMC4618684, DOI: 10.1016/j.ccell.2015.02.003.Peer-Reviewed Original ResearchMeSH KeywordsBasic Helix-Loop-Helix Transcription FactorsClinical Trials as TopicDNA-Binding ProteinsGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMolecular Sequence DataPhosphatidylinositol 3-KinasePre-B-Cell Leukemia Transcription Factor 1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-6Signal TransductionSrc-Family KinasesSyk KinaseUp-RegulationConceptsDistinct subtypesPre-BCR signalingPatient-derived preVivo treatment studiesTreatment of patientsAcute lymphoblastic leukemiaTyrosine kinase inhibitorsPre-B cell receptor signalingCell receptor signalingLymphoblastic leukemiaClinical trialsTreatment studiesPre-BCR functionReceptor signalingKinase inhibitorsDistinct subsetsBCL6 expressionInduced activationFeedback activationSubtypesTyrosine kinaseBCL6SignalingActivationTranscriptional level