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
Neurological Sciences Training Initial Review Group (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
Linzey, Joseph R; Marini, Bernard L; Pasternak, Amy et al. (2018) Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology. J Neurooncol 137:155-169
Linzey, Joseph R; Marini, Bernard; McFadden, Kathryn et al. (2018) Erratum: Author Correction: Identification and targeting of an FGFR fusion in a pediatric thalamic ""central oligodendroglioma"". NPJ Precis Oncol 2:12
Pratt, Drew; Natarajan, Siva Kumar; Banda, Adam et al. (2018) Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol 135:299-301
Yadav, Viveka Nand; Altshuler, David; Kadiyala, Padma et al. (2018) Molecular ablation of tumor blood vessels inhibits therapeutic effects of radiation and bevacizumab. Neuro Oncol 20:1356-1367
Stallard, Stefanie; Savelieff, Masha G; Wierzbicki, Kyle et al. (2018) CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response. Acta Neuropathol Commun 6:80
Pratt, Drew; Camelo-Piragua, Sandra; McFadden, Kathryn et al. (2018) BRAF activating mutations involving the ?3-?C loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma. Acta Neuropathol Commun 6:24
Gits, Hunter C; Anderson, Maia; Stallard, Stefanie et al. (2018) Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry. Acta Neuropathol Commun 6:67
Koschmann, Carl; Nunez, Felipe J; Mendez, Flor et al. (2017) Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer. Cancer Res 77:227-233
Linzey, Joseph R; Marini, Bernard; McFadden, Kathryn et al. (2017) Identification and targeting of an FGFR fusion in a pediatric thalamic ""central oligodendroglioma"". NPJ Precis Oncol 1:29
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

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