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 这是终身教授助理教授 Lapo Alinari 博士提出的 K08 职业发展奖提案 俄亥俄州立大学 (OSU) 血液学系的跟踪。 Alinari 博士将投入至少 75% 他的时间主要集中在关于转导蛋白 β 样蛋白 1 (TBL1) 在套细胞中的作用的研究项目 淋巴瘤 (MCL) 和相关转化研究，其余 25% 通过 8 周住院治疗 服务。俄勒冈州立大学 (OSU) 拥有国际公认的血液癌症研究项目和 血液学在培养成功的医师科学家方面拥有良好的记录。 Alinari 博士拥有多元化的 拥有良好业绩记录的指导团队，包括 John C. Byrd 博士（转化科学）、Natarajan 博士 Muthusamy（基础科学、免疫学）和 Kevin Coombes 博士（基因组学/生物信息学）提供建议和 支持他的研究目标和职业发展计划。该团队将得到顾问的补充 委员会由 Robert A. Baiocchi 博士（转化性淋巴瘤）和 Kristie A. Blum 博士（临床 淋巴瘤）。 Alinari 博士的职业发展计划建立在他之前的研究经验之上，包括 正式课程，以加深他在基因组学、生物信息学、免疫学、药物开发方面的知识 作为专业发展活动，旨在加强人际网络、提高手稿/赠款写作技能 目标是成为一名专注于 MCL 的独立转化研究者。 MCL 是一种侵袭性亚型 B 细胞 NHL 仍无法治愈。 Wnt/β 连环蛋白信号通路在许多疾病中被异常激活 包括 MCL 在内的癌症，并通过调节 Wnt 靶基因促进肿瘤细胞存活。瞄准β 连环蛋白由于其结构的复杂性和许多脱靶效应而未能成功。 迄今为止测试的化合物。 TBL1 是一种 E3 泛素连接酶，可与 β 连环蛋白结合以促进其转录 活动。本研究项目的目的是从功能上表征 TBL1 在 MCL 中的作用，以 验证 TBL1 作为该疾病临床前模型中的新治疗靶点，并研究其分子机制 TBL1 的小分子抑制剂 tegatrabetan 诱导 MCL 细胞死亡的机制。这 其基本原理是 TBL1 作为转录调节剂的关键作用在 MCL 中尚未得到探索。阿利纳里博士的 初步数据显示，与正常免疫细胞相比，MCL细胞核表达高水平的TBL1 并且对 TBL1 抑制非常敏感，表明 TBL1 是该领域潜在的新型治疗靶点 疾病。核心假设是 TBL1 促进 MCL 细胞不受控制的增殖和存活 通过其双重能力激活 Wnt/β 连环蛋白靶基因的转录，同时抑制 肿瘤抑制/调节基因，并且通过 tegatrabetan 抑制 TBL1 将通过以下方式促进 MCL 细胞死亡： TBL1 转录程序的调节。这里完成的工作将提供有关 TBL1 函数的数据 并促进替加曲贝坦的临床开发。从这些临床前研究中获得的数据将 用于申请额外资金以支持 MCL 患者中替加曲贝坦的 I 期临床试验。