Rational Translation of EZH2 Targeted Therapy in Germinal Center B-cell Lymphoma

EZH2靶向治疗生发中心B细胞淋巴瘤的合理转化

• 批准号: 9370942
• 负责人: Lisa Giulino Roth
• 金额: $ 17.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-06 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370942
• 关键词: Adult; Advisory Committees; Affinity; Antigens; Award; B-Cell Lymphomas; B-Lymphocytes; Biological Markers; Biology; Burkitt Lymphoma; Cells; Clinical; Clinical Trials; Clonal Expansion; Collaborations; Combined Modality Therapy; Cytotoxic Chemotherapy; Dependence; Development; Differentiated Gene; Disease remission; Dose; Drug Combinations; EZH2 gene; Epigenetic Process; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Lymphoma; Evolution; Experimental Designs; Future; Gene Expression Profile; Genes; Genetic Engineering; Genetic Transcription; Genomic Instability; Genomics; Goals; Grant; Growth; Human; Human Herpesvirus 4; Immune; Immune Evasion; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Immunologic Surveillance; International; Investigational Therapies; Joints; Kinetics; Laboratories; Lead; Leadership; Link; Lymphoma; Lytic; Maximum Tolerated Dose; Mediating; Mentors; Mentorship; Methods; Oncogenic; Organoids; Patients; Pediatric Oncologist; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Play; Positioning Attribute; Pre-Clinical Model; Primary Neoplasm; Public Speaking; Refractory Disease; Relapse; Reporting; Repression; Research; Research Personnel; Research Proposals; Role; Schedule; Scientist; Structure; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Agents; Time; Training; Training Programs; Translations; Viral; Viral Genes; Viral Proteins; Virus Latency; Work; Xenograft procedure; base; career; career development; cell killing; chemotherapy; clinical development; design; disease mechanisms study; drug development; epigenomics; gain of function mutation; histone methyltransferase; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; medical schools; meetings; mouse model; mutant; mutational status; novel; novel therapeutics; pharmacodynamic biomarker; phase I trial; plasma cell differentiation; professor; protein expression; response; self-renewal; skills; small molecule inhibitor; synergism; targeted agent; targeted treatment; tumor; tumor growth

This proposal describes a 5-year training program designed to enable the applicant to develop an independent research career in the field of lymphoma biology and experimental therapeutics. The applicant is a pediatric oncologist at Weill Cornell Medical College (WCMC) who is committed to an academic career studying disease mechanisms in lymphoma and exploiting these mechanisms to develop novel therapies. Her current research focuses on targeting the histone methyltransferase EZH2 in B-cell lymphoma. The candidate’s immediate career goals are to gain further training in experimental design and develop expertise in epigenomics. Her long-term career goals are to establish independent laboratory space, lead a team of researchers, and make scientific contributions that allow her develop into a national/international leader in the field. To enable these goals this proposal outlines the following career development objectives: 1) formal training in experimental design, drug development, and statistical genomics; 2) coursework in epigenetic dysregulation, 3) regular meetings with an advisory committee composed of distinguished clinicians, scientists, and institutional leaders; 4) formal and informal professional development in leadership, management skills, public speaking and grantsmanship. The applicant’s mentors, Dr. Ethel Cesarman and Dr. Ari Melnick, are both tenured professors at WCMC and are international leaders in the study of viral-related lymphomas and epigenetic mechanisms in lymphoma respectively. Dr. Cesarman and Dr. Melnick have an extensive track record of collaboration including multiple joint grant awards and joint mentorship of trainees. The research proposal focuses on the rational translation of EZH2 targeted therapy in germinal center (GC) B-cell lymphomas. GC B-cell lymphomas are aggressive tumors that occur in pediatrics and adults. Relapsed/refractory disease represents an unmet need with most treatments failing to induce durable remissions. GC B-cell lymphomas are dependent on EZH2 which is a lineage factor for germinal center B-cells. EZH2 may play a unique role in EBV+ lymphoma where it contributes to restricted EBV viral latency that allows immune evasion. Small molecule inhibitors of EZH2 are currently in clinical development, including GSK126, which is being studied in a phase I trial that the applicant is conducting in collaboration with GSK. The unique mechanism and time course of epigenetic therapy requires careful consideration for effective clinical deployment. The overarching goal of this proposal is to develop a rational approach for the clinical use of EZH2i in lymphoma. The specific aims are 1) Define the epigenetic and transcriptional background of lymphomas that respond to EZH2 inhibition (EZH2i); 2) Determine the kinetics of response to EZH2i and the point of maximum vulnerability to combination therapy; 3) Determine the impact of EZH2i on the vulnerability of EBV + lymphomas to immune mediated therapy. Overall this proposal will accomplish the rational evolution and deployment of a new class of therapeutic agents in lymphoma. This work will be the basis of future clinical trials, which the applicant will be positioned to lead.

该提案描述了一项为期5年的培训计划，旨在为申请人开发独立 淋巴瘤生物学和实验疗法领域的研究职业。 威尔·康奈尔医学院（WCMC）的肿瘤科医生致力于祖先手术疾病 淋巴瘤的机制和这些机制开发了她当前的研究 旨在靶向B细胞淋巴瘤中的组蛋白甲基转移酶EZH2 职业目标是获得实验设计的进一步培训，并在表观基因组学方面发展专业知识 长期职业目标是建立独立的实验室空间，领导一组研究人员，并使 科学贡献使她成为该领域的国家/国际领导者 目标本提案概述了以下职业发展目标：1）实验中的正规培训 设计，药物开发和统计基因组学； 2）表观遗传失调的课程 与咨询委员会的会议由杰出的临床医生，科学家和工厂领袖组成； 4）领导，管理技能，公开演讲和非正式专业发展和非正式的专业发展 授予申请人的导师Ethel Cesarman和Ari Melnick博士都是 在WCMC，是研究与病毒相关淋巴瘤和表观遗传机制研究的国际领导者 淋巴瘤分别 包括多个联合赠款奖和对学员的联合指导。 EZH2靶向治疗（GC）B细胞淋巴瘤的有理翻译 是在儿科和成人中发生的侵略性肿瘤。 大多数治疗方法都无法诱导耐用的gc b-细胞淋巴瘤 这是发芽中心B细胞的谱系因子。 有助于限制EBV病毒潜伏期，从而允许IMUNE逃避。 目前正在临床开发中，包括GSK126，该申请人正在I期中研究 正在与GSK合作进行。 需要仔细考虑有效的临床部署。 开发一种在淋巴瘤中临床使用EZH2I的方法。 淋巴瘤的表观遗传和转录背景对EZH2的反应（EZH2I）； 对EZH2I的反应的动力学和最大的组合治疗脆弱性； 3） EZH2I对EBV +淋巴瘤对免疫介导的治疗的脆弱性的影响。 提案将完成一类新的治疗剂的理性演变和部署 淋巴瘤。