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

髓母细胞瘤中的 B7-H3：评估其表达和功能以利用新的治疗靶点

• 批准号: 10374119
• 负责人: Allison M Martin
• 金额: $ 19.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374119
• 关键词: Address; Animal Model; Antibodies; Bioinformatics; Biostatistical Methods; Blocking Antibodies; Blood - brain barrier anatomy; Bone Marrow; CD276 gene; CRISPR/Cas technology; Cell Cycle; Cell Death Induction; Cells; Characteristics; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinical; Clinical Trials; Color; Contralateral; Data; Detection; Disease; Doctor of Philosophy; Enzyme-Linked Immunosorbent Assay; Face; Family; Flow Cytometry; Foundations; Future; Generations; Genomics; Growth; Histology; Human; Immune; Immune checkpoint inhibitor; Immune mediated destruction; Immune system; Immunocompetent; Immunohistochemistry; Immunologist; Immunology; Implant; In Vitro; Inflammatory; Knockout Mice; Knowledge; Learning; Literature; Malignant Childhood Neoplasm; Malignant neoplasm of brain; Medical center; Medicine; Mentors; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Mutate; Neuraxis; Neurosciences; Oncogenes; Oncologist; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Pediatric Oncology; Phase I Clinical Trials; Phenotype; Physicians; Population; Production; Prognosis; Program Development; Publishing; Recurrent disease; Refractory; Relapse; Reporting; Research; Risk; Sampling; Scientist; Subgroup; Survivors; TP53 gene; Techniques; Testing; Therapeutic; Therapy Evaluation; Tissue Microarray; Toxic effect; Treatment Efficacy; Tumor Tissue; Tumor-infiltrating immune cells; Universities; Wild Type Mouse; Work; anti-tumor immune response; antitumor agent; c-myc Genes; cancer therapy; career development; checkpoint therapy; college; cytokine; design; efficacy evaluation; genome editing; immune checkpoint; immunoregulation; improved; in vivo; interest; knock-down; medulloblastoma; medulloblastoma cell line; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; preclinical evaluation; programmed cell death ligand 1; programs; single cell analysis; single-cell RNA sequencing; skills; standard care; stem; success; therapeutic target; tool; tumor; tumor-immune system interactions

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.

项目总结/摘要 这份提案概述了一个5年的职业发展计划，旨在进一步我的研究计划， 免疫检查点分子在儿科脑肿瘤中的功能和潜在治疗效用， 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 我热衷于为约25%的肿瘤对化疗无反应的儿童寻找新的治疗方法。 标准治疗且无法治愈。该提案建立在我之前评估表达的研究基础上 并产生MYC驱动的间变性MB的同基因动物模型， 疾病我以前发现MB中PD-L1表达缺乏，迄今为止， 靶向该途径的抗体尚未取得显著成功。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）/Montefiore Medical的项目 中心（MMC）的机会，与我的导师，XingXing Zang，博士研究新的B7家族免疫 检查点分子B7-H3，其在MB中高度表达并且代表有吸引力的治疗靶标。 本提案的科学目的是评估B7-H3阻断抗体作为治疗的有效性 并为未来的临床试验奠定临床前基础。为了实现这一目标，我将在我的研究B7-H3 在小鼠MB模型以及经典的人MB细胞系和人MB患者样品中。这些研究 来源于报告人MB中B7-H3的已发表文献和我自己的初步数据， 在我的模型中。我将得到我的导师臧博士的大力支持，他开发了 本研究的翻译B7-H3阻断抗体以及在肿瘤中敲低B7-H3的工具， 浸润的免疫细胞。这个项目的目的是完成我的科学目标，并提供 我有额外的知识和技能，启动一个完全独立的儿科脑肿瘤研究 程序.我将通过参加研究生课程来增加我的免疫学和神经科学知识， 我与免疫学家臧博士和我的共同导师，医学博士，神经科学家伊马德·埃斯坎达进行了交流。我会 获得新的技能，重要的是完成这个项目，也将有助于我在未来的研究工作 包括骨髓嵌合小鼠的产生和单细胞RNA-seq数据的分析。我会 参加基因组学和生物信息学课程，熟悉基因组学技术， 正确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 独立的医学科学家