Year: 2017
Type: conference-abstract
Abstract: High-grade gliomas (HGGs), including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are the most aggressive malignant high-grade gliomas in children, and are incurable with current therapies. The most frequent genetic lesions that drive formation of HGGs include amplification/overexpression, mutation, and/or activation of receptor tyrosine kinases (RTK), such as PDGFRA, and K27M mutations in histone H3 proteins. We have discovered that the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) transcriptional activators, which encode paralogous transcriptional activators, are frequently overexpressed in RTK-mutant/overexpressing pediatric HGGs. We have also discovered that YAP/TAZ activity is required for to promote stemness and self-renewal in tumor cells. We hypothesize that, because of oncogenic RTK alterations, YAP/TAZ become constitutively activated to drive a gene expression program that promotes uncontrolled expansion of neural stem/progenitor cells to create malignant tumors, and that this can be exacerbated by H3-K27M epigenetic dysregulation. In testing this hypothesis, we have generated compelling preliminary data showing that pharmacologic inhibition of YAP/TAZ activity specifically provokes growth arrest and cell death of RTK-overexpressing HGG cells, particularly in the context of H3-K27M mutations. Our ongoing research is focused on identifying the YAP/TAZ transcriptional program that drives tumorigenesis. Our research indicates that YAP/TAZ inhibition may be a promising therapeutic strategy for pediatric HGGs.
Source: Neuro-Oncology
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2767845151