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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.

项目总结/文摘

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

Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma.

CSF无细胞肿瘤DNA的电子DNA分析，以量化小儿高级神经胶质瘤中的多基因分子反应。

DOI：
10.1158/1078-0432.ccr-20-2066
发表时间：
2020-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Bruzek AK;Ravi K;Muruganand A;Wadden J;Babila CM;Cantor E;Tunkle L;Wierzbicki K;Stallard S;Dickson RP;Wolfe I;Mody R;Schwartz J;Franson A;Robertson PL;Muraszko KM;Maher CO;Garton HJL;Qin T;Koschmann C
通讯作者：
Koschmann C

Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

DOI：
10.1007/s11912-020-0877-0
发表时间：
2020-02-06
期刊：
Current oncology reports
影响因子：
4.7
作者：
Wierzbicki K;Ravi K;Franson A;Bruzek A;Cantor E;Harris M;Homan MJ;Marini BL;Kawakibi AR;Ravindran R;Teodoro R;Yadav VN;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。