Targeting ATRX-Deficient Pediatric GBM

针对 ATRX 缺陷的儿童 GBM

基本信息

批准号：
10055776
负责人：
Carl J Koschmann
金额：
$ 15.83万
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/10055776
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 Prognosis 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 checkpoint inhibition 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 neoantigens neoplastic cell neuro-oncology new therapeutic target novel novel therapeutics 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 Koschmann 博士是一位通过精准医学方法治疗儿童胶质母细胞瘤 (GBM) 的突变。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通过进行本提案中的实验，Koschmann 博士将获得这些关键的信息。新的技能组合，同时产生的数据将促进我们对 ATRX 突变/丢失的作用的理解这项研究将在主要导师玛丽亚·卡斯特罗博士和由在职业生涯中取得广泛指导的杰出医学科学家组成的顾问委员会。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和五年内不断进步的科学独立性是脑肿瘤的关键。 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 的治疗无效且无效。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最近的体细胞突变。肿瘤测序显示，30% 的儿童 GBM 中组蛋白伴侣 ATRX 发生突变， Koschmann 博士之前对至少 15 种其他人类癌症的研究表明，ATRX 的缺失会导致受损。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的治疗能力，该提案将在两个具体目标中进行测试。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)；以及 (2) ATRX 缺陷 GBM 中的突变负担将产生 HLA- Koschmann 博士将认识到神经胶质瘤新抗原适合未来的免疫检查点抑制。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 缺陷总而言之，该提案将产生非常需要的内容。此外，这项工作将提高我们对儿科 GBM 的理解和治疗。将为 Koschmann 博士提供创建独立研究项目所需的技能，该项目实施开发儿童/青少年 GBM 疗法的精准医学方法。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brainstem Low-Grade Gliomas in Children-Excellent Outcomes With Multimodality Therapy.

DOI：
10.1177/0883073816675547
发表时间：
2017-03
期刊：
Journal of child neurology
影响因子：
1.9
作者：
Upadhyaya SA;Koschmann C;Muraszko K;Venneti S;Garton HJ;Hamstra DA;Maher CO;Betz BL;Brown NA;Wahl D;Weigelin HC;DuRoss KE;Leonard AS;Robertson PL
通讯作者：
Robertson PL

Integrating RNA sequencing into neuro-oncology practice.

DOI：
10.1016/j.trsl.2017.06.013
发表时间：
2017-11
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
0
作者：
Rogawski DS;Vitanza NA;Gauthier AC;Ramaswamy V;Koschmann C
通讯作者：
Koschmann C

Multiplatform Molecular Profiling: A Precision Medicine Victory Built on Cytotoxic Chemotherapy.

多平台分子分析：基于细胞毒性化疗的精准医学胜利。

DOI：
10.1097/ppo.0000000000000359
发表时间：
2019
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
0
作者：
Cantor,Evan;Koschmann,Carl
通讯作者：
Koschmann,Carl

Identification and targeting of an FGFR fusion in a pediatric thalamic "central oligodendroglioma".

DOI：
10.1038/s41698-017-0036-8
发表时间：
2017
期刊：
NPJ precision oncology
影响因子：
7.9
作者：
Linzey JR;Marini B;McFadden K;Lorenzana A;Mody R;Robertson PL;Koschmann C
通讯作者：
Koschmann C

Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology.

DOI：
10.1007/s11060-017-2708-1
发表时间：
2018-03
期刊：
Journal of neuro-oncology
影响因子：
3.9
作者：
Linzey JR;Marini BL;Pasternak A;Smith C;Miklja Z;Zhao L;Kumar-Sinha C;Paul A;Harris N;Robertson PL;Hoffman LM;Chinnaiyan A;Mody R;Koschmann C
通讯作者：
Koschmann C