Targeting ATRX-Deficient Pediatric GBM

针对 ATRX 缺陷的儿童 GBM

• 批准号: 9223317
• 负责人: Carl J Koschmann
• 金额: $ 16.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223317
• 关键词: ATRX gene; Adult; Adult Glioblastoma; Adult Glioma; Aftercare; Age; Alleles; Animal Model; Antibody Therapy; Antigens; Binding; Bioinformatics; Biological Assay; Biology; Brain Neoplasms; Cancer Etiology; Cell Cycle Progression; Cell Proliferation; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioblastoma; Collaborations; Communities; Competence; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Data Set; Defect; Development Plans; Diagnosis; Doctor of Philosophy; Epigenetic Process; Foundations; Future; Generations; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Histones; Human; Impairment; In Vitro; Induced Mutation; Investigation; MHC Class I Genes; Malignant Neoplasms; Mentors; Mentorship; Methodology; Michigan; Molecular Chaperones; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nonhomologous DNA End Joining; Pathway Analysis; Pathway interactions; Pediatric Neoplasm; Physicians; Plasmids; Positioning Attribute; Proteins; Publishing; Radiation; Radiation therapy; Recurrence; Regimen; Reporter; Research; Role; Scientist; Sleeping Beauty; Somatic Mutation; System; Techniques; Testing; Training; Transplantation; Universities; Western Blotting; Work; age group; ataxia telangiectasia mutated protein; base; cancer genomics; cancer pharmacology; career; career development; childhood cancer mortality; design; exome sequencing; experimental study; genome sequencing; homologous recombination; immune checkpoint; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; innovation; mouse model; neoplastic cell; neuro-oncology; new therapeutic target; novel; novel therapeutics; outcome forecast; patient population; pediatric patients; pre-clinical; precision medicine; programs; repaired; response; skills; success; targeted agent; temozolomide; therapeutic target; therapy design; therapy development; tumor; whole genome; young adult

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.

项目概要/摘要 这项 K08 提案将进一步促进医学博士 Carl Koschmann 的培训，以实现他的长期职业目标：提高 通过研究针对复发的能力，我们对儿童脑肿瘤的理解和治疗 通过精准医学方法治疗儿童胶质母细胞瘤（GBM）突变。科施曼博士是 密歇根大学的小儿神经肿瘤学医师科学家已经建立了一个 存在于他的领域。该提案建立在 Koschmann 博士之前获得的临床前专业知识的基础上 神经胶质瘤和癌症药理学动物模型，经过 DNA 损伤修复途径分析新训练 和生物信息学。通过进行本提案中的实验，Koschmann 博士将获得这些关键的 新的技能组合，同时产生的数据将促进我们对 ATRX 突变/丢失的作用的理解 儿科 GBM。这项研究将在主要导师玛丽亚·卡斯特罗博士和 由具有广泛指导成功经验的医学科学家组成的顾问委员会。职业生涯 该提案中概述的发展包括教育课程、将科施曼博士纳入 科学界，以及五年内不断进步的科学独立性。脑肿瘤是 20岁以下儿童癌症相关死亡的主要原因，胶质母细胞瘤代表大脑 儿童和成人预后最差的肿瘤。儿童 GBM 的治疗无效且 基于针对成人 GBM 设计的治疗方案，该治疗方案具有独特的生物学和体细胞突变。最近的 肿瘤测序显示，30% 的儿童 GBM 中组蛋白伴侣 ATRX 发生突变， 至少 15 种其他人类癌症。 Koschmann 博士之前的研究表明 ATRX 的缺失会导致功能受损 非同源末端连接（NHEJ）和增加的肿瘤体细胞突变。然而，没有研究表明 探索了针对这些新发现进行治疗的能力。在两个具体目标中，该提案将测试 假设：(1) ATRX 缺陷的 GBM 中 NHEJ 的丢失将导致对靶向药物的敏感性增加 同源重组（HR）； (2) ATRX 缺陷 GBM 中的突变负担将产生 HLA- 公认的神经胶质瘤新抗原适合未来的免疫检查点抑制。科施曼博士将 非常适合通过使用以下方法来探索这些问题：(1) ATRX 缺陷的新型小鼠模型 GBM，(2) 最先进的癌症基因组/生物信息学技术，以及 (3) 新颖的 DNA 损伤疗法。 这项工作将构建多个未来的 R01 提案，包括：(1) 确定免疫检查点是否 阻断疗法对 ATRX 缺陷的 GBM 有效，并且（2）探索潜在的表观遗传机制 ATRX 损失导致 NHEJ 缺陷。总之，该提案将创造急需的 转化数据将提高我们对儿科 GBM 的理解和治疗。另外，这项工作 将为 Koschmann 博士提供创建独立研究项目所需的技能，该项目实施 开发儿科/青少年 GBM 疗法的精准医学方法。