Diffuse intrinsic pontine glioma (DIPG) is a brain tumor most commonly diagnosed in children of median age 6-7 and the prognosis is very poor. The ten percent survival after two years is less than 2 years. The tumor originates in the pons, but is highly invasive. Due to its sensitive location and invasive nature, the tumor cannot be removed surgically. Chemotherapy and radiation are the only treatment options; however no effective chemotherapy has been found. Thus, studying the intrinsic biology of this tumor is imperative for the design of improved molecularly targeted therapies. This proposal will utilize the information gained from genomic studies of autopsy and biopsy tissue that revealed the presence of recurrent gain of function mutations in ACVR1 and dominant negative K27M mutations in the genes encoding histone H3 variants, H3.3 and H3.1. ACVR1 is a serine-threonine kinase transmembrane signal transduction protein of the bone morphogenetic pathway (BMP); however, it is unknown how altered BMP signaling affects DIPG pathogenesis. The dominant negative mutation occurring in Histone H3.1 and H3.3 variants results in a global loss and redistribution of histone H3K27 tri- methylation which consequently affects gene expression. This proposal will use a genetically engineered immunocompetent mouse model to address the role of ACVR1 G328V and commonly co-expressed H3.1 K27M on DIPG pathogenesis and will seek to understand their impact on the tumor response to DNA damaging agents. In summary, the studies included in this proposal will generate novel translational data relevant to patients with ACVR1 and H3.1 mutations. Our results will aid in the design of future targeted therapies for treatment of DIPG.

Public Health Relevance

In order to design effective therapies for children with diffuse intrinsic pontine glioma (DIPG) a better understanding of the tumor biology is needed. This proposal will explore mechanisms by which activating ACVR1 mutations and dominant negative H3K27M mutations affect DIPG tumorigenesis and DNA repair pathways. The overall goal of this work is to test if DNA repair mechanisms are altered in DIPGs with these genetic alterations in order to develop novel agents that exploit the biology of the tumor.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Fountain, Jane W
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University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
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Haase, Santiago; Garcia-Fabiani, María Belén; Carney, Stephen et al. (2018) Mutant ATRX: uncovering a new therapeutic target for glioma. Expert Opin Ther Targets 22:599-613
Mendez, Flor M; Núñez, Felipe J; Zorrilla-Veloz, Rocío I et al. (2018) Native Chromatin Immunoprecipitation Using Murine Brain Tumor Neurospheres. J Vis Exp :