Targeting ATRX-Deficient Pediatric GBM

项目摘要/摘要 这份K08提案将进一步推动卡尔·科什曼的训练，朝着他职业生涯的长期目标不断提高 从靶向复发能力的调查看儿童脑肿瘤的认识和治疗 通过精确医学方法检测儿童胶质母细胞瘤(GBM)的突变。科什曼博士是一位 密歇根大学儿科神经肿瘤学内科科学家，他已经建立了一个 出现在他的田野里。这项建议建立在科什曼博士之前在临床前获得的专业知识的基础上 新的DNA损伤修复途径分析训练的胶质瘤动物模型和肿瘤药理学 和生物信息学。通过执行这项提案中的实验，科什曼博士将获得这些关键的 新的技能，同时产生数据，将促进我们对ATRX突变/丢失在 儿科GBM。这项研究将在主要导师玛丽亚·卡斯特罗、博士和 一个由有成就的内科科学家组成的顾问委员会，并取得了广泛的指导成功。职业生涯 这项提案中概述的发展包括教育课程工作，将科什曼博士纳入 科学共同体，并在五年内逐步实现科学独立。脑瘤是 20岁以下儿童癌症相关死亡的主要原因，脑胶质母细胞瘤 儿童和成人预后最差的肿瘤。儿童GBM的治疗无效且 基于为成人GBM设计的方案，GBM具有明显的生物学和体细胞突变。近期 肿瘤测序显示，组蛋白伴侣ATRX在30%的儿童GBM和AT中发生突变 至少还有15种其他人类癌症。Koschmann博士之前的工作表明，ATRX的丢失会导致 非同源末端连接(NHEJ)和肿瘤体细胞突变增加。然而，没有研究表明 探索了在治疗上针对这些新发现的能力。在两个具体目标上，这项提案将考验 假设：(1)ATRX缺乏的GBM中NHEJ的缺失将导致对靶向药物的敏感性增加 同源重组(HR)；以及(2)ATRX缺陷的GBM的突变负荷将产生HLA- 已识别的胶质瘤新抗原，可用于未来的免疫检查点抑制。科什曼博士将成为 通过使用：(1)一种新的ATRX缺陷小鼠模型 (2)最先进的癌症基因组/生物信息学技术，以及(3)新的DNA损伤疗法。 这项工作将建立在未来R01提案的基础上，包括：(1)确定免疫检查点 阻断治疗对ATRX缺乏的GBM是有效的，以及(2)探索潜在的表观遗传学机制 ATRX的丢失导致NHEJ的缺陷。总而言之，这项提案将创造非常需要的 翻译数据将提高我们对儿童GBM的认识和治疗。此外，这项工作 将为科什曼博士提供所需的技能，以创建一个独立的研究计划，实现 精准医学方法在儿童/青壮年基底细胞瘤治疗中的应用

PROJECT SUMMARY/ABSTRACT This K08 proposal will further Carl Koschmann, MD’s training towards his long-term career goal of improving our understanding and treatment of pediatric brain tumors by investigation of the ability to target recurrent mutations in pediatric glioblastoma (GBM) through a precision medicine approach. Dr. Koschmann is a Pediatric Neuro-Oncology physician scientist at the University of Michigan who has already established a presence in his field. This proposal builds on Dr. Koschmann’s previously acquired expertise in pre-clinical animal models of glioma and cancer pharmacology with new training in DNA damage repair pathway analysis and bioinformatics. By carrying out the experiments in this proposal, Dr. Koschmann will obtain these critical new skillsets while producing data that will advance our understanding of the role of ATRX mutation/loss in pediatric GBM. This research will be conducted under the guidance of primary mentor Maria Castro, PhD and an advisory board of accomplished physician scientists with extensive mentoring success. The career development outlined in this proposal includes educational coursework, integration of Dr. Koschmann into a scientific community, and progressive scientific independence over a five-year period. Brain tumors are the leading cause of cancer-related deaths in children under the age of 20, and glioblastoma represents the brain tumor with the poorest prognosis in children and adults. Treatments for pediatric GBM are ineffective and based on regimens designed for adult GBM, which harbor distinct biology and somatic mutations. Recent tumor sequencing has revealed that the histone chaperone ATRX is mutated in 30% of pediatric GBMs and at least 15 other human cancers. Previous work by Dr. Koschmann showed that loss of ATRX results in impaired non-homologous end joining (NHEJ) and increased tumor somatic mutations. However, no studies have explored the ability to therapeutically target these novel findings. In two Specific Aims, this proposal will test the hypothesis that: (1) loss of NHEJ in ATRX-deficient GBM will result in increased sensitivity to agents that target homologous recombination (HR); and (2) mutational burden in ATRX-deficient GBM will generate HLA- recognized glioma neo-antigens amenable to future immunologic checkpoint inhibition. Dr. Koschmann will be ideally positioned to explore these questions through the use of: (1) a novel mouse model of ATRX-deficient GBM, (2) state-of-the-art cancer genomic/bioinformatic techniques, and (3) novel DNA-damaging therapies. This work will build to multiple future R01 proposals, including to: (1) to determine if immunologic checkpoint blockade therapy is effective in ATRX-deficient GBM, and (2) to explore the potential epigenetic mechanisms by which ATRX loss leads to a defect in NHEJ. In summary, this proposal will create highly needed translational data that will improve our understanding and treatments of pediatric GBM. Additionally, this work will provide Dr. Koschmann with the skills needed to create an independent research program that implements a precision medicine approach in the development of therapies for pediatric/young adult GBM.