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，旨在使申请人能够培养独立​​的能力 淋巴瘤生物学和实验治疗学领域的研究生涯。申请人是儿科 威尔康奈尔医学院 (WCMC) 的肿瘤学家，致力于疾病研究的学术生涯 淋巴瘤的机制，并利用这些机制开发新的疗法。她目前的研究 专注于针对 B 细胞淋巴瘤中的组蛋白甲基转移酶 EZH2。候选人的即时 职业目标是获得实验设计方面的进一步培训并发展表观基因组学方面的专业知识。她 长期的职业目标是建立独立的实验室空间，带领研究团队，做出 科学贡献使她成为该领域的国家/国际领导者。要启用这些 目标 本提案概述了以下职业发展目标： 1) 实验方面的正式培训 设计、药物开发和统计基因组学； 2) 表观遗传失调课程，3) 常规课程 与由杰出临床医生、科学家和机构领导人组成的咨询委员会举行会议； 4) 领导力、管理技能、公开演讲和 赠款。申请人的导师Ethel Cesarman博士和Ari Melnick博士均为终身教授 在 WCMC，是病毒相关淋巴瘤和表观遗传机制研究的国际领导者 分别为淋巴瘤。塞萨曼博士和梅尔尼克博士有着广泛的合作记录 包括多项联合资助和对学员的联合指导。该研究计划的重点是 EZH2 靶向治疗在生发中心 (GC) B 细胞淋巴瘤中的合理转化。 GC B细胞淋巴瘤 是发生于儿科和成人的侵袭性肿瘤。复发/难治性疾病代表着未得到满足的疾病 大多数治疗未能引起持久缓解。 GC B 细胞淋巴瘤依赖于 EZH2 这是生发中心 B 细胞的谱系因子。 EZH2 可能在 EBV+ 淋巴瘤中发挥独特作用 有助于限制 EBV 病毒潜伏期，从而允许免疫逃避。 EZH2 的小分子抑制剂是 目前正处于临床开发阶段，其中包括 GSK126，该药物正在 I 期试验中进行研究，申请人表示 正在与 GSK 合作进行。表观遗传治疗独特的机制和时程 需要仔细考虑有效的临床部署。该提案的总体目标是 制定 EZH2i 在淋巴瘤临床应用的合理方法。具体目标是 1) 定义 对 EZH2 抑制（EZH2i）有反应的淋巴瘤的表观遗传和转录背景； 2）确定 对 EZH2i 的反应动力学和联合治疗的最大脆弱点； 3）确定 EZH2i 对 EBV + 淋巴瘤对免疫介导治疗的脆弱性的影响。总体来说这个 该提案将完成一类新型治疗药物的合理进化和部署 淋巴瘤。这项工作将成为未来临床试验的基础，申请人将领导该试验。