Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML

描述 AML 中 Wilms 肿瘤 1 (WT1) 突变的发病机制和靶向治疗

• 批准号: 10451996
• 负责人: Haijiao Zhang
• 金额: $ 24.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451996
• 关键词: Characterizing; pathogenesis; targeted; therapeutics; Wilms

PROJECT SUMMARY/ABSTRACT Dr. Haijiao Zhang has been training as a medical student for 7 years with a focus on hematological malignancies and as a researcher for 6 years in the field of characterizing oncogene and drug resistance mechanisms. Her research has led to 8 published manuscripts and 4 other manuscripts in submission /preparation. The theme of Dr. Zhang's research involves systematic characterization of leukemia oncogenes and understanding leukemia drug resistance mechanisms. She has characterized 4 distinct mechanisms of CSF3R mutations and diverse mechanisms associated with drug resistance to the FLT3 inhibitor crenolanib. The WT1 (Wilms' tumor 1) gene encodes a transcription factor with C-terminal zinc-finger domains, whereas the N-terminal part contains domains that mediate receptor dimerization, RNA recognition, and transcriptional regulation. WT1 mutations are present in approximately 10–15% of AML and are associated with chemotherapy resistance and disease relapse. WT1 mutations are frameshift mutations or substitutions across all structural domains, predominantly in exons 7 and 9. The pathogenesis mediated by loss-of-function of WT1 zinc finger domain mutations has been studied; however very little is known about the oncogenic potential, drug sensitivity, and the structural basis of mutations residing in other domains of WT1. In the current proposal, Dr. Zhang will evaluate the functional consequences of these mutations and characterize the mechanisms associated with the growth/survival advantage and a higher propensity for chemotherapy resistance of WT1 mutations. She also aims to identify therapeutics with enhanced efficacy in the WT1 mutant setting. Using ex vivo inhibitor screening on primary leukemia patient samples, she has determined that inhibitors of BCL2 and RAF/ERK pathways demonstrated higher efficacy against WT1 mutant samples compared with controls. She will validate these findings using NRG mouse model. Finally, she will investigate the phenotypic, mechanistic, and therapeutics targeting WT1 combinatorial mutation. Dr. Zhang's long-term career goals include the establishment of an independent research lab focusing on systematic characterization of oncogenic mutations and chemotherapy resistance to better predict the clinical relevance of mutations and identify novel therapeutics to circumvent chemotherapy resistance. During the mentored phase, she will continue to receive excellent mentorship from Dr. Jeffrey Tyner, an expert on functional genomics and targeted therapy. She will receive co-mentorship from Dr. Ravi Majeti, an expert in leukemia stem cell biology, CRISPR editing, and high-fidelity xenotransplantation mouse models, which she will use in the current project. The proposed research will also be enhanced by guidance from Dr. Brian Druker, a pioneer in translational medicine and targeted therapies for cancer; and Dr. Shannon McWeeney who will provide guidance in bioinformatics analyses. Additionally, Dr. Tyner, Dr. Majeti, and the advisory team will assist her in navigating the transition to an independent faculty position.

项目摘要/摘要 张海娇医生已经作为医科学生接受了7年的培训，重点是血液学 在癌基因和耐药领域从事了6年的研究工作 机制。她的研究产生了8篇已发表的手稿和4篇提交的其他手稿 /准备。张博士的研究主题涉及白血病癌基因的系统表征 以及了解白血病耐药机制。她描述了四种不同的机制 CSF3R突变和与Flt3抑制剂crenolanib耐药相关的不同机制。 WT1(Wilms‘s Tumor 1)基因编码一个带有C-末端锌指结构域的转录因子，而 N-末端部分包含介导受体二聚化、RNA识别和转录的结构域 监管。WT1突变存在于大约10%-15%的AML中，并与 化疗耐药和疾病复发。WT1突变是移码突变或替换 所有结构域，主要位于外显子7和9。WT1功能丧失所介导的发病机制 锌指结构域突变已被研究；然而，对致癌潜力知之甚少。 药物敏感性，以及WT1其他区域突变的结构基础。在目前的提案中， 张博士将评估这些突变的功能后果，并描述其机制 与WT1的生长/存活优势和化疗耐药倾向相关 突变。她还致力于找出在WT1突变环境中具有增强疗效的治疗方法。使用EX 在对原发白血病患者样本进行体内抑制物筛选时，她已经确定bcl2和bcl2的抑制物 与对照相比，RAF/ERK通路对WT1突变型样本显示出更高的效率。她 将使用NRG小鼠模型验证这些发现。最后，她将研究表型、机械性、 以及针对WT1组合突变的治疗药物。 张博士的长期职业目标包括建立一个独立的研究实验室，专注于 系统分析癌基因突变和化疗耐药性以更好地预测临床 突变的相关性，并确定新的治疗方法，以规避化疗耐药性。 在指导阶段，她将继续得到专家杰弗里·泰纳博士的极好指导 关于功能基因组学和靶向治疗。她将得到拉维·马吉蒂博士的共同指导，拉维·马杰蒂博士是一位 白血病干细胞生物学、CRISPR编辑和高保真异种移植小鼠模型，她 将在当前项目中使用。这项拟议的研究还将在布莱恩·德鲁克博士的指导下得到加强， 转化医学和癌症靶向治疗的先驱；香农·麦克维尼博士 提供生物信息学分析方面的指导。此外，泰纳博士、马盖蒂博士和咨询团队将 帮助她顺利过渡到独立的教职员工职位。