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.

项目总结/摘要 这K 08建议将进一步卡尔Koschmann，医学博士的培训，朝着他的长期职业目标，提高 通过研究针对复发性脑肿瘤的能力， 通过精准医学方法研究儿童胶质母细胞瘤（GBM）的基因突变。科施曼博士是一位 密歇根大学的儿科神经肿瘤学医生科学家已经建立了一个 存在于他的领域。该提案建立在Koschmann博士先前在临床前研究方面获得的专业知识基础上， 神经胶质瘤和癌症药理学的动物模型与DNA损伤修复途径分析的新培训 和生物信息学。通过执行本提案中的实验，Koschmann博士将获得这些关键的 新的技能，同时产生的数据，将促进我们的理解的作用ATRX突变/损失 小儿GBM。这项研究将在初级导师玛丽亚·卡斯特罗博士的指导下进行， 一个由有成就的医生科学家组成的顾问委员会，他们在指导方面取得了广泛的成功。职业 该提案中概述的发展包括教育课程，将Koschmann博士融入一个 科学界，并在五年内逐步实现科学独立。脑肿瘤是 胶质母细胞瘤是20岁以下儿童癌症相关死亡的主要原因， 儿童和成人预后最差的肿瘤。儿科GBM的治疗无效， 基于为成年GBM设计的方案，其具有不同的生物学和体细胞突变。最近 肿瘤测序显示组蛋白伴侣ATRX在30%的儿童GBM中发生突变， 至少15种其他人类癌症。Koschmann博士以前的工作表明，ATRX的丧失导致受损的 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 探索了治疗这些新发现的能力。在两个具体目标中，该提案将测试 假设：（1）ATRX缺陷GBM中NHEJ的缺失将导致对靶向 同源重组（HR）;和（2）ATRX缺陷GBM中的突变负荷将产生HLA- 识别的胶质瘤新抗原适合于未来的免疫检查点抑制。科斯曼博士将在 理想地定位于通过使用以下来探索这些问题：（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，和（3）新型DNA损伤疗法。 这项工作将建立在多个未来的R 01建议，包括：（1）以确定是否免疫检查点， 阻断治疗对ATRX缺陷的GBM有效，（2）探索潜在的表观遗传机制 由此ATRX损失导致NHEJ中的缺陷。总之，这项提案将创造高度必要的 翻译数据，将提高我们的理解和治疗小儿GBM。此外，这项工作 将为Koschmann博士提供创建独立研究计划所需的技能， 一种精确的医学方法，用于开发儿科/年轻成人GBM的治疗方法。