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的K08职业发展奖提案，医学博士，终身教职助理教授 在俄亥俄州立大学(OSU)血液科追踪。阿利纳里博士将投入至少75% 他参与了一项关于转导蛋白β样蛋白1在套细胞中的作用的重点研究计划 淋巴瘤(MCL)和相关的翻译研究，其余25%的患者住院8周 服务。俄亥俄州立大学有一个国际公认的血液学癌症研究计划和 血液学在培养成功的内科科学家方面有着出色的记录。Alinari医生有一种不同的 具有良好业绩记录的指导团队，包括John C.Byrd博士(翻译科学)、Natarajan博士 Muthusamy(基础科学、免疫学)和Kevin Coombs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。这个团队将得到一个咨询意见的补充 由Robert A.Baiocchi博士(转化性淋巴瘤)和Kristie A.Blum博士(临床)组成的委员会 淋巴瘤)。Alinari博士的职业发展计划建立在他以前的研究经验基础上，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 作为职业发展活动，以加强网络联系，提高手稿/赠款写作技能 成为一名专注于MCL的独立翻译调查员的目标。MCL是一种侵袭性亚型 B细胞性非霍奇金淋巴瘤，至今仍无法治愈。Wnt/β连环蛋白信号通路在许多疾病中异常激活 包括MCL在内的肿瘤，并通过调节WNT靶基因促进肿瘤细胞存活。目标β 由于其复杂的结构和许多偏离目标的作用，连环蛋白一直没有成功 到目前为止测试过的化合物。TbL1是一种E3泛素连接酶，可与β连环蛋白结合，促进其转录 活动。这项研究的目的是从功能上表征TbL1在MCL中的作用，以 在本病的临床前模型中验证TBL1作为一种新的治疗靶点，并研究其分子 TBL1小分子抑制剂替加曲贝坦诱导MCL细胞死亡的机制这个 其基本原理是，在MCL中，TBL1作为转录调控因子的关键作用尚不清楚。阿利纳里医生的 初步数据显示，与正常免疫细胞相比，MCL细胞表达高水平的TBL1 并且对TBL1的抑制非常敏感，这表明TBL1是一种潜在的新的治疗靶点 疾病。中心假设是TBL1促进MCL细胞的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 肿瘤抑制基因/调控基因以及通过替加曲坦抑制TBL1将促进MCL细胞的死亡 TbL1转录程序的调控。在此完成的工作将提供有关TBL1函数的数据 促进替加曲坦的临床发展。从这些临床前研究中获得的数据将 用于申请额外资金，以支持替加曲贝坦在MCL患者中的I期临床试验。