CSIG-30. CHARACTERIZING THE OVER-EXPRESSION OF Yki/YAP/TAZ TRANSCRIPTION FACTORS IN GLIOMAGENESIS AND A PROPOSED NOVEL TREATMENT OF GLIOBLASTOMAS
Year: 2017
Type: conference-abstract
Abstract: Glioblastomas (GBMs) are among the most common primary malignant brain tumors in adults and are resistant to current therapies. The most frequent genetic lesions in GBMs include amplification, mutation, and/or over expression of receptor tyrosine kinases (RTKs) and mutations that constitutively activate the PI-3 kinase (PI3K) pathway. Using a novel RNAi screen in a Drosophila model of RTK-driven glioblastoma, our lab has previously reported conserved kinase pathways required for tumor growth. We have recently focused on the Hippo kinase pathway and it downstream targets, the Yki-YAP/TAZ transcription factors, which normally control stem/progenitor cell proliferation and self-renewal in several tissues. Our preliminary data reveal that YAP and TAZ become overexpressed in tumor cells with RTK amplification or mutation, and that YAP/TAZ drive GBM cell proliferation and survival. We hypothesize that, as a consequence of RTK activity, YAP and/or TAZ become overexpressed and activated to constitutively drive a transcriptional program that provokes an uncontrolled expansion of mutant neural stem/progenitor cells to create malignant glial tumors. YAP and/or TAZ promote the initiation and progression of other tumor types and several published studies show that pharmacologic inhibition of YAP and TAZ blocks tumor cell growth in vitro and in animal models. In testing this hypothesis, we have generated data that demonstrates that pharmacologic inhibition of YAP and TAZ specifically elicits growth arrest and apoptosis in GBM cells, and rapidly alters the expression of transcriptional target genes required for tumor cell survival in GBM cells. We are now testing the therapeutic potential of YAP/TAZ inhibition in GBMs driven by RTK mutations.
Source: Neuro-Oncology
Institutions: Emory University, Winship Cancer Institute
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2767438103