CSIG-26. MET FUSION, AMPLIFICATION, AND/OR OVEREXPRESSION DEFINES DIFFUSELY INVASIVE TUMOR CELLS IN PEDIATRIC AND ADULT GLIOBLASTOMA

Abstract

Glioblastomas (GBMs) are WHO Grade IV neoplasms of the central nervous system (CNS) that are the most common and most aggressive glioma. Genomics show that the most frequent changes in GBMs include amplification, mutation, and/or overexpression of receptor tyrosine kinases (RTKs) as well as mutations that constitutively activate the PI-3 kinase (PI3K) pathway. Current data indicates that RTK-PI3K signaling cooperates with other mutations that drive GBM pathology and confer therapeutic resistance. To best understand the factors that drive tumor growth and therapeutic resistance, we have developed a research program that utilizes primary human GBM neurosphere cultures created from surgical specimens. These GBM neurosphere cultures retain many of the defining features and mutations found in primary tumors, and, in mouse xenograft assays, they yield highly malignant invasive tumors. We currently have more than 30 GBM neurosphere lines created from tumors that have been genomically profiled for copy number abnormalities and for common mutations. In addition, neurosphere lines are subject to RNA sequencing to determine their over-all transcriptome and to identify novel and recurrent mutations in tumor cells. Through these analyses we have identified a number of copy number changes, point mutations, and gene fusions in several loci. We identified alterations in the MET gene, and found that diffusely invasive GBM cells express MET. Our sequencing data showed that MET is co-overexpressed with Class 3 Semaphorins and their receptors, genes that augment MET activity in migrating neural cells in the developing embryonic brain; these genes may cooperate with MET alterations to worsen GBM. Therefore, we propose to 1) test drugs that inhibit MET and in our models of MET-mutant GBMs, and 2) determine if MET mutations and alterations cooperate with Semaphorins to drive GBM tumor cell invasion. Our results could lead to new clinical trials of MET targeted therapies in GBM.