Tenascin-C as a Therapeutic Target in Pediatric Brainstem Glioma

Diffuse intrinsic pontine glioma (DIPG) is the most deadly solid tumor in children, with rapid progression, poor response to therapy, and average survival less than one year from diagnosis. There is no effective treatment, and all children diagnosed with DIPG will die of this cancer. We recently identified increased expression of Tenascin-C (TNC), an extracellular matrix protein, in DIPG tumor tissue and cerebrospinal fluid (CSF). TNC overexpression correlated with Histone H3 K27M mutation, which occurs in up to 80% of DIPGs and is known to alter global epigenetic control of gene transcription. Here, we propose a hypothesis-driven research plan to elucidate the mechanism by which Tenascin-C (TNC) contributes to pediatric brainstem glioma (DIPG) formation and progression. TNC overexpression promotes glioma formation in adults, and facilitates cell proliferation and migration during brain development through pathways known to contribute to gliomagenesis in children. However, TNC overexpression in DIPG has not been previously reported. The findings of this proposal will be the first to demonstrate the role of TNC expression in formation of pediatric brainstem glioma (DIPG), providing novel insight to the mechanism of tumorigenesis and a potential for developing rational, effective treatment for children with this disease.