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: 10092821
• 负责人: Lapo Alinari
• 金额: $ 22.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10092821
• 关键词: Address; Advisory Committees; Agammaglobulinaemia tyrosine kinase; Apoptotic; Autologous Stem Cell Transplantation; B Cell Proliferation; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Basic Science; Binding; Bioinformatics; Cancer Research Project; Cell Death; Cell Line; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Complement; Complex; Data; Development; Development Plans; Disease; Disease model; Doctor of Philosophy; Drug Utilization; Epigenetic Process; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Grant; Hematologic Neoplasms; Hematology; Human; Immune; Immuno-Chemotherapy; Immunology; International; K-Series Research Career Programs; Knowledge; Lymphoma; Lymphoma cell; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Manuscripts; Mediating; Mentors; Molecular; Molecular Target; Natural Killer Cells; Nuclear; Ohio; Oncogenic; Outcome; Pathway interactions; Patients; Pharmacology; Phase I Clinical Trials; Physicians; Pre-Clinical Model; Prognosis; Proteins; Refractory; Regimen; Regulator Genes; Relapse; Research; Research Project Grants; Role; Scientist; Signal Pathway; Signal Transduction; Specificity; Structure; T-Lymphocyte; TNF gene; Testing; Time; Training; Transducin; Translational Research; Tumor Suppressor Proteins; Universities; Up-Regulation; Work; Writing; Xenograft procedure; base; beta catenin; career development; chemotherapy; clinical development; drug development; experience; immune function; improved; improved outcome; in vivo Model; inhibitor/antagonist; inpatient service; lenalidomide; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; pre-clinical; preclinical study; professor; programs; response; rituximab; skills; small molecule; small molecule inhibitor; tenure track; therapeutic target; translational scientist; tumor; tumorigenic; ubiquitin-protein ligase

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 这是Lapo Alinari，MD，PhD的K08职业发展奖提案，任期助理教授 俄亥俄州立大学（OSU）血液学系的轨道。 Alinari博士至少专用于75％ 他的时间是针对透明蛋白β样蛋白1（TBL1）在地幔细胞中的作用的重点研究计划 淋巴瘤（MCL）和相关的转化研究，其余25％在住院期间服务 服务。 OSU具有国际认可的血液学癌症研究计划和分区 血液学在培训成功的身体科学家方面具有良好的记录。 Alinari博士有潜水员 指导团队具有可靠的记录，包括约翰·C·伯德（John C. Byrd）博士（翻译科学） Muthusamy（基础科学，免疫学）和Kevin Coombes博士（基因组/生物信息学）建议和建议 在他的研究目标和职业发展计划中支持他。该团队将由咨询 由Robert A. Baiocchi博士（翻译淋巴瘤）和Kristie A. Blum博士组成的委员会（临床 淋巴瘤）。 Alinari博士的职业发展计划基于他的先前研究经验，包括 正式课程，以进一步了解他对基因组学，生物信息学，免疫学，药物开发的了解 作为增强网络的专业发展活动，提高手稿/赠款写作技巧 成为专注于MCL的独立翻译研究人员的目标。 MCL是一种积极的亚型 B-cell NHL的无法治愈。 Wnt/βcatenin信号通路在许多人中被异常激活 包括MCL在内的癌症，并通过调节Wnt靶基因促进肿瘤细胞的存活。靶向β 由于其结构的复杂性和许多关闭目标影响 迄今为止测试的化合物。 TBL1是一种E3泛素连接酶，与β链氨酸结合以促进其转录 活动。该研究项目的目的是在功能上表征TBL1在MCL中的作用， 在该疾病的临床前模型中验证TBL1作为一种新的治疗靶标，并研究分子 TBL1的小分子抑制剂Tegatrabetan诱导MCL细胞死亡。这 理由是，在MCL中，TBL1作为转录调制器的关键作用是出乎意料的。 Alinari博士 初步数据表明，与正常的免疫细胞相比，MCL细胞表达高核水平TBL1 并且对TBL1抑制完全敏感，这表明TBL1是潜在的新型治疗靶标 疾病。中心假设是TBL1促进了MCL细胞的不受控制的增殖和存活率 通过其双重能力激活Wnt/β链氨酸蛋白靶基因的转录，同时反映了 肿瘤抑制剂/调节基因和通过Tegatrabetan抑制TBL1将通过 调制TBL1转录程序。这里完成的工作将提供有关TBL1功能的数据 在MCL中并促进Tegatrabetan的临床发展。从这些临床前研究获得的数据将 用于申请额外的资金，以支持MCL患者的Tegatrabetan进行I期临床试验。