Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
基本信息
- 批准号:10092821
- 负责人:
- 金额:$ 22.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdvisory CommitteesAgammaglobulinaemia tyrosine kinaseApoptoticAutologous Stem Cell TransplantationB Cell ProliferationB-Cell NonHodgkins LymphomaB-LymphocytesBasic ScienceBindingBioinformaticsCancer Research ProjectCell DeathCell LineCell SurvivalCellsClinicClinicalClinical TrialsComplementComplexDataDevelopmentDevelopment PlansDiseaseDisease modelDoctor of PhilosophyDrug UtilizationEpigenetic ProcessFundingFutureGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomicsGoalsGrantHematologic NeoplasmsHematologyHumanImmuneImmuno-ChemotherapyImmunologyInternationalK-Series Research Career ProgramsKnowledgeLymphomaLymphoma cellMalignant - descriptorMalignant NeoplasmsMantle Cell LymphomaManuscriptsMediatingMentorsMolecularMolecular TargetNatural Killer CellsNuclearOhioOncogenicOutcomePathway interactionsPatientsPharmacologyPhase I Clinical TrialsPhysiciansPre-Clinical ModelPrognosisProteinsRefractoryRegimenRegulator GenesRelapseResearchResearch Project GrantsRoleScientistSignal PathwaySignal TransductionSpecificityStructureT-LymphocyteTNF geneTestingTimeTrainingTransducinTranslational ResearchTumor Suppressor ProteinsUniversitiesUp-RegulationWorkWritingXenograft procedurebasebeta catenincareer developmentchemotherapyclinical developmentdrug developmentexperienceimmune functionimprovedimproved outcomein vivo Modelinhibitor/antagonistinpatient servicelenalidomidemouse modelneoplastic cellnew therapeutic targetnovelnovel therapeutic interventionoverexpressionpre-clinicalpreclinical studyprofessorprogramsresponserituximabskillssmall moleculesmall molecule inhibitortenure tracktherapeutic targettranslational scientisttumortumorigenicubiquitin-protein ligase
项目摘要
Project abstract
This is a K08 career development award proposal from Lapo Alinari, MD, PhD, an Assistant Professor on Tenure
Track in the Division of Hematology at the Ohio State University (OSU). Dr. Alinari will devote a minimum of 75%
of his time to a focused research program on the role of transducin β-like protein 1 (TBL1) in mantle cell
lymphoma (MCL) and related translational research, with the remaining 25% served through 8 weeks of inpatient
service. OSU has an internationally recognized hematologic cancer research program and the Division of
Hematology has an excellent record of training successful physician-scientists. Dr. Alinari has a diverse
mentoring team with a proven track record, including Dr. John C. Byrd (translational science), Dr. Natarajan
Muthusamy (basic science, immunology), and Dr. Kevin Coombes (genomics/bioinformatics) to advise and
support him in his research aims and career development plan. This team will be complemented by an advisory
committee consisting of Dr. Robert A. Baiocchi (translational lymphoma) and Dr. Kristie A. Blum (clinical
lymphoma). Dr. Alinari’s career development plan builds upon his prior research experience and includes
formal coursework to further his knowledge of genomics, bioinformatics, immunology, drug development as well
as professional development activities to enhance networking, improve manuscript/ grant writing skills with
the goal of becoming an independent translational investigator focusing on MCL. MCL is an aggressive subtype
of B-cell NHL which remains incurable. The Wnt/β catenin signaling pathway is aberrantly activated in many
cancers including MCL, and promotes tumor cell survival through modulation of Wnt target genes. Targeting β
catenin has been unsuccessful due to the complexity of its structure and to the many off target effects of the
compounds tested thus far. TBL1 is an E3 ubiquitin ligase that binds to β catenin to promote its transcriptional
activity. The objective of this research project is to functionally characterize the role of TBL1 in MCL, to
validate TBL1 as a novel therapeutic target in preclinical models of this disease, and to study the molecular
mechanism through which tegatrabetan, a small molecule inhibitor of TBL1, induces MCL cell death. The
rationale is that the critical role of TBL1 as a transcriptional modulator is unexplored in MCL. Dr. Alinari’s
preliminary data show that, in contrast to normal immune cells, MCL cells express high nuclear levels of TBL1
and are exquisitely sensitive to TBL1 inhibition, suggesting TBL1 is a potential novel therapeutic target in this
disease. The central hypothesis is that TBL1 promotes the uncontrolled proliferation and survival of MCL cells
through its dual ability to activate transcription of Wnt/β catenin target genes while repressing transcription of
tumor suppressor/regulatory genes and that TBL1 inhibition via tegatrabetan will promote MCL cell death through
modulation of the TBL1 transcriptional program. The work accomplished here will provide data on TBL1 function
in MCL and promote the clinical development of tegatrabetan. Data obtained from these preclinical studies will
be used to apply for additional funding to support a phase I clinical trial with tegatrabetan in MCL patients.
项目摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Lapo Alinari其他文献
Lapo Alinari的其他文献
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{{ truncateString('Lapo Alinari', 18)}}的其他基金
Trispecific CAR-T cells targeting CD19, CD20 and CD22 to treat B-cell malignancies
靶向 CD19、CD20 和 CD22 的三特异性 CAR-T 细胞治疗 B 细胞恶性肿瘤
- 批准号:
10735096 - 财政年份:2023
- 资助金额:
$ 22.7万 - 项目类别:
Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
- 批准号:
10594537 - 财政年份:2022
- 资助金额:
$ 22.7万 - 项目类别:
Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
- 批准号:
10342915 - 财政年份:2022
- 资助金额:
$ 22.7万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
9505524 - 财政年份:2018
- 资助金额:
$ 22.7万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
10360452 - 财政年份:2018
- 资助金额:
$ 22.7万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10553341 - 财政年份:1997
- 资助金额:
$ 22.7万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10333297 - 财政年份:1997
- 资助金额:
$ 22.7万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10090012 - 财政年份:1997
- 资助金额:
$ 22.7万 - 项目类别:
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