Targeting transducin Beta-like protein 1 in mantle cell lymphoma

项目摘要 这是一个K 08职业发展奖的建议，从拉波Alinari，医学博士，博士，助理教授任期 在俄亥俄州州立大学（OSU）血液学部跟踪。阿利纳里博士将投入至少75%的 他的时间集中在一个关于转导素β样蛋白1（TBL 1）在套细胞中的作用的研究项目上 淋巴瘤（MCL）和相关的转化研究，其余25%通过8周的住院治疗 的服务.俄勒冈州立大学有一个国际公认的血液学癌症研究计划， 血液学在培养成功的医生科学家方面有着良好的记录。Alinari博士有一个多样化的 指导团队具有良好的业绩记录，包括博士约翰C。Byrd（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， 支持他的研究目标和职业发展计划。该小组将得到一名顾问的补充， 由罗伯特·A博士组成。Baiocchi（转化淋巴瘤）和Kristie A.博士。百隆（临床 淋巴瘤）。Alinari博士的职业发展计划建立在他以前的研究经验之上，包括 正式的课程，以进一步他的基因组学，生物信息学，免疫学，药物开发以及 作为专业发展活动，以加强网络，提高手稿/赠款写作技能， 目标是成为一名专注于MCL的独立翻译研究者。MCL是一种攻击性亚型 B细胞非霍奇金淋巴瘤，至今无法治愈Wnt/β catenin信号通路在许多细胞中被异常激活， 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。靶向β 连环蛋白由于其结构的复杂性和其许多脱靶效应而不成功。 到目前为止测试的化合物。TBL 1是一种E3泛素连接酶，其结合β连环蛋白以促进其转录 活动本研究的目的是从功能上描述TBL 1在MCL中的作用， 在这种疾病的临床前模型中验证TBL 1作为新的治疗靶点，并研究其分子生物学特性。 TBL 1的小分子抑制剂tegatrabetan诱导MCL细胞死亡的机制。的 基本原理是TBL 1作为转录调节剂的关键作用在MCL中尚未探索。Alinari博士的 初步数据显示，与正常免疫细胞相比，MCL细胞表达高核水平的TBL 1 并且对TBL 1的抑制非常敏感，这表明TBL 1是一个潜在的新的治疗靶点。 疾病中心假设是TBL 1促进MCL细胞的不受控制的增殖和存活 通过其激活Wnt/β连环蛋白靶基因转录同时抑制Wnt/β连环蛋白靶基因转录的双重能力， 肿瘤抑制/调节基因，并且通过tegatrabetan抑制TBL 1将促进MCL细胞死亡， TBL 1转录程序的调节。本文的工作将为TBL 1的功能研究提供数据 促进替加贝坦的临床开发。从这些临床前研究中获得的数据将 用于申请额外的资金，以支持在MCL患者中进行tegatrabetan的I期临床试验。

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.