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

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)
专利数量(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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