Targeting ATRX-Deficient Pediatric GBM

针对 ATRX 缺陷的儿童 GBM

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要这项K08提案将进一步进一步，医学博士卡尔·科什曼（Carl Koschmann）培训他的长期职业目标，以改善我们通过投资靶向复发能力的投资对小儿脑肿瘤的理解和治疗小儿胶质母细胞瘤（GBM）的突变通过精确的医学方法。 Koschmann博士是密歇根大学的儿科神经肿瘤学物理科学家在他的领域。该提案建立在Koschmann博士以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，具有新的DNA损伤修复途径分析的新培训和生物信息学。通过在此提案中进行实验，Koschmann博士将获得这些关键新技能集在产生数据的同时，可以提高我们对ATRX突变/损失作用的理解小儿GBM。这项研究将在主要导师玛丽亚·卡斯特罗（Maria Castro），博士和成熟的身体科学家顾问委员会取得了广泛的心理成功。职业该提案中概述的发展包括教育课程，将科斯曼博士整合到一个科学界和五年内的进步科学独立性。脑肿瘤是 20岁以下儿童与癌症相关死亡的主要原因，而胶质母细胞瘤代表大脑儿童和成人预后最差的肿瘤。小儿GBM治疗无效，基于为成人GBM设计的方案，该方案具有独特的生物学和体细胞突变。最近的肿瘤测序表明，组蛋白伴侣ATRX在30％的小儿GBM和AT中突变至少15种人类癌症。 Koschmann博士的先前工作表明，ATRX的损失导致受损非理论末端连接（NHEJ）和肿瘤体细胞突变增加。但是，没有研究探索了对这些新发现的热靶向的能力。在两个具体目标中，该提案将测试假设：（1）ATRX缺陷GBM中NHEJ的丢失将导致对靶向药物的敏感性提高同源重组（HR）；（2）缺乏ATRX的GBM中的突变烧伤将产生HLA- 公认的神经瘤新抗原可与未来的免疫学检查点抑制相应。 Koschmann博士将理想的位置可以通过使用：（1）ATRX缺陷的新型鼠标模型来探索这些问题 GBM，（2）最先进的癌症基因组/生物信息学技术和（3）新型DNA损害疗法。这项工作将对未来的R01提案进行构建，包括：（1）确定免疫学检查点是否是封锁治疗对ATRX缺陷GBM有效，（2）探索潜在的表观遗传机制 ATRX损失导致NHEJ缺陷。总而言之，该提议将创造急需的翻译数据将改善我们对小儿GBM的理解和治疗。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针对儿科/年轻成人GBM疗法开发的精确医学方法。