Targeting GSK3B in refractory B-cell malignancies
Targeting GSK3B in refractory B-cell malignancies
批准号:
10720232
负责人:
Markus Müschen
金额:
$61.01万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-19 至 2028-06-30
关键词:
AcuteAdhesionsAllelesB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-Cell LeukemiaB-Cell NeoplasmB-LymphocytesCell AdhesionCell DeathCell Death InductionCell NucleusCell membraneClinical TrialsComplexDataDeacetylationDiseaseDrug CombinationsDrug resistanceE-CadherinElementsEngineeringEnhancersEpithelial CellsExclusion CriteriaExonsFutureGene ExpressionGenesGeneticGlucocorticoidsGoalsHumanIn VitroKnock-inLabelLesionLymphoidMalignant - descriptorMalignant NeoplasmsMalignant lymphoid neoplasmMantle Cell LymphomaMediatingMutationNuclearNucleosomesOncogenicPatientsPhosphorylationRefractoryRegulationRepressionRepressor ProteinsResistanceRoleSafetySignal TransductionSolid NeoplasmT-LymphocyteTestingTherapeuticTherapeutic InterventionTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationTreatment ProtocolsTumor SuppressionZinc Fingerscancer typecell transformationclinical developmentexperimental studygene repressiongenome editinghumanized mousein vivoinhibitorleukemia/lymphomaloss of function mutationlymphoid neoplasmmembermouse modelnanomolarnervous system disordernew therapeutic targetnovel strategiespatient derived xenograft modelpatient subsetspre-clinicalresponsesmall moleculesmall molecule inhibitorstem cellstranscription factor
中文摘要
摘要
英文摘要
Abstract
GSK3E functions as essential negative regulator of E-catenin, while E-catenin accumulation represents a central
oncogenic driver in cancer. In solid tumors, E-catenin forms complexes with TCF7-factors for transcriptional
activation of MYC1-5. In striking contrast to solid tumors, we found that B-cell leukemias and lymphomas are not
only exempt from activating E-catenin lesions but highly sensitive to E-catenin accumulation and critically depend
on its negative regulation by GSK3E-mediated degradation: Unlike other cancer types, inducible activation of E-
catenin in B-cell malignancies suppressed MYC-expression and rapidly induced cell death. Instead of the
transcriptional activator TCF7, our interactome studies in B-cell malignancies revealed that E-catenin formed a
repressive complex with lymphoid-specific Ikaros zinc finger (IKZF)6-8 factors. Instead of MYC-activation, E-
catenin assembled lymphoid-specific Ikaros factors and multiple members of the repressive nucleosome
remodeling and deacetylation (NuRD)9-10 complex for transcriptional repression of MYC.
GSK3E phosphorylates S/T-residues in E-catenin exon 3, to initiate E-catenin- degradation. To leverage
lymphoid-specific repressive E-catenin-complexes as previously unrecognized therapeutic vulnerability, we
examined GSK3E small molecule inhibitors. Strikingly, established GSK3E-inhibitors that are currently in clinical
trials for the neurological disorders and solid tumors, were effective at low nanomolar concentrations in B-cell
malignancies, induced massive accumulation of E-catenin, repression of MYC and acute cell death. Preclinical
experiments based on patient-derived xenografts validated small molecule GSK3E-inhibitors for targeted
engagement of lymphoid-specific repressive E-catenin-complexes to overcome drug-resistance in refractory B-
cell malignancies in vivo.
Based on this discovery, the central goal of this proposal is to repurpose GSK3E-inhibitors for targeted
engagement of repressive E-catenin-complexes in refractory B-cell malignancies. Given that four GSK3E-
inhibitors have already undergone full clinical development and demonstrated favorable safety profiles in
eighteen clinical trials, we anticipate that this powerful new approach can rapidly be developed to benefit patients
with refractory B-cell malignancies and be further extended to T-cell malignancies in the future. We propose two
Aims to (1) elucidate the mechanistic basis of E-catenin-mediated tumor suppression and to (2) develop concepts
to leverage targeted activation of E-catenin-Ikaros complexes for therapeutic intervention in refractory B-cell
malignancies.
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