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.

Public Health Relevance

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 this age group. Recent tumor sequencing has shown that pediatric glioblastomas (GBMs) harbor distinct recurrent mutations from adult GBMs, including frequent mutation in the histone chaperone ATRX. Determination of our ability to therapeutically target ATRX loss would both: (1) help improve the design of treatments for pediatric patients with GBM, and (2) improve our understanding of this driver of multiple human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS099427-02
Application #
9391712
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2016-12-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chandran, Mayuri; Candolfi, Marianela; Shah, Diana et al. (2017) Single vs. combination immunotherapeutic strategies for glioma. Expert Opin Biol Ther 17:543-554
Upadhyaya, Santhosh A; Koschmann, Carl; Muraszko, Karin et al. (2017) Brainstem Low-Grade Gliomas in Children-Excellent Outcomes With Multimodality Therapy. J Child Neurol 32:194-203
Koschmann, Carl; Nunez, Felipe J; Mendez, Flor et al. (2017) Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer. Cancer Res 77:227-233
Rogawski, David S; Vitanza, Nicholas A; Gauthier, Angela C et al. (2017) Integrating RNA sequencing into neuro-oncology practice. Transl Res 189:93-104
Bruzek, Amy K; Zureick, Andrew H; McKeever, Paul E et al. (2017) Molecular characterization reveals NF1 deletions and FGFR1-activating mutations in a pediatric spinal oligodendroglioma. Pediatr Blood Cancer 64:
Marini, Bernard L; Benitez, Lydia L; Zureick, Andrew H et al. (2017) Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors. Transl Res 188:27.e1-27.e14
Linzey, Joseph R; Marini, Bernard L; Pasternak, Amy et al. (2017) Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology. J Neurooncol :
Tran, Dustin; Camelo-Piragua, Sandra; Gupta, Avneesh et al. (2017) Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor. J Pediatr Hematol Oncol 39:e466-e469