B7-H3 in Medulloblastoma: evaluating its expression and function to harness new therapeutic targets

项目摘要/摘要 这份提案概述了一项为期5年的职业发展计划，旨在将我的研究计划深入到 免疫检查点分子在儿童脑肿瘤中的作用及潜在治疗作用 髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤。作为一名儿科神经肿瘤学家，我 我热衷于为~25%的肿瘤无反应的儿童寻找新的治疗方法 标准的治疗方法，无法治愈。这项建议建立在我之前评估表达式的研究基础上 PD-L1在MB中的表达，并建立MYC驱动的模拟复发的间变性MB的同基因动物模型 疾病。我之前发现在MB中PD-L1的表达很少，到目前为止，临床试验 针对这一途径的抗体尚未取得重大成功。因此，我把我的研究 从约翰霍普金斯大学到阿尔伯特·爱因斯坦医学院(AECOM)/蒙特菲奥里医学院的课程 中心(MMC)有机会与我的导师臧兴兴合作，研究新的B7家族免疫 检查点分子B7-H3，在MB中高表达，代表着一个有吸引力的治疗靶点。 这项建议的科学目标是评估B7-H3封闭抗体作为一种治疗方法的疗效 为MB奠定临床前基础，为未来临床试验奠定基础。为了做到这一点，我将在我的 小鼠MB模型以及经典的人MB细胞系和人MB患者样本。这些研究 来源于已发表的关于人MB中B7-H3的文献报道和我自己的初步数据证明其 在我的模型中表达。我将得到我的导师Zang博士的大力支持，他开发了 本研究的翻译B7-H3封闭抗体以及在肿瘤和肿瘤组织中击倒B7-H3的工具 正在渗透的免疫细胞。这个项目的目的是为了完成我的科学目标和提供 我拥有额外的知识和技能来启动一项完全独立的儿科脑瘤研究 程序。我会通过参加研究生课程来增加我的免疫学和神经科学知识 与免疫学家Zang博士和我的共同导师、神经学家Emad Eskandar医学博士进行了互动.这就做 获得对完成这个项目很重要的新技能，这些技能也将在未来的研究工作中服务于我 包括骨髓嵌合小鼠的产生，以及单细胞RNA-SEQ数据的分析。这就做 参加基因组学和生物信息学课程，熟悉基因组学技术，学习 用适当的生物统计学方法来解释它们。这些重要的技能将为我的未来奠定基础 一位独立的内科科学家。

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5 year career development program designed to further my research program into the function and potential therapeutic utility of immune checkpoint molecules in the pediatric brain tumor, medulloblastoma (MB), the most common malignant brain tumor in children. As a pediatric neuro-oncologist, I am passionate about finding novel therapies for the ~25% of children whose tumors do not respond to standard treatment and have no cure. This proposal builds on my previous research evaluating the expression of PD-L1 in MB and generating a syngeneic animal model of MYC-driven anaplastic MB that mimics recurrent disease. I previously found that there was a paucity of PD-L1 expression in MB and thus far clinical trials of antibodies targeting this pathway have not met with significant success. Therefore, I moved my research program from Johns Hopkins University to Albert Einstein College of Medicine (AECOM)/Montefiore Medical Center (MMC) for the opportunity to work with my mentor, XingXing Zang, PhD on the novel B7 family immune checkpoint molecule, B7-H3, which is highly expressed in MB and represents an attractive therapeutic target. The scientific objective of this proposal is to evaluate the efficacy of B7-H3 blocking antibodies as a treatment for MB and lay the preclinical foundation for a future clinical trial. To accomplish this, I will study B7-H3 in my murine MB model as well as in classic human MB cell lines, and human MB patient samples. These studies stem from published literature reporting B7-H3 in human MB and my own preliminary data demonstrating its expression in my model. I will have strong support from my mentor, Dr. Zang, who has developed the translational B7-H3 blocking antibodies for this study as well as tools to knock down B7-H3 in the tumor and in the infiltrating immune cells. The purpose of this project is to both complete my scientific aims and to provide me with the additional knowledge and skills to launch a fully independent pediatric brain tumor research program. I will increase my immunology and neuroscience knowledge by participating in graduate courses and interacting with Dr. Zang an immunologist, and my co-mentor, Emad Eskandar, MD, a neuroscientist. I will obtain new skills important to the completion of this project that will also serve me in future research endeavors including the generation of bone marrow chimeric mice, and the analysis of single-cell RNA-seq data. I will participate in genomics and bioinformatics courses to familiarize myself with genomics techniques and learn the proper biostatistical methods to interpret them. These important skills will lay the foundation for my future an independent physician scientist.