CNSC-76. NEUROPHYSIOLOGIC SMALL MOLECULE SCREEN FOR INHIBITORS OF NEURAL VULNERABILITIES IN DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline glioma (DMG) is a devastating brain tumor affecting children and adults with life expectancy of one year and no effective treatment. As a tumor that arises from glial precursors, DMG hijacks neurophysiological signaling pathways present in the healthy and developing brain. Signals conferred by neurotransmitters and ion channels promote glioma proliferation and enhance its invasion throughout the brain. Additionally, neuronal activity in the tumor environment induces secretion of paracrine factors that potently stimulate glioma growth. Multiple types of neurons form bona fide synapses with glioma cells, inducing depolarizing postsynaptic currents that increase glioma proliferation. We are investigating neural vulnerabilities in DMG via a small molecule drug screening approach. We curated a custom library of 327 compounds targeting neurotransmitter receptors and transporters, ion channels, and other neurophysiological signaling nodes. Many of the compounds are in use or under development for a variety of neuropsychiatric conditions. We performed small molecule screens on a panel of patient-derived DMG cell lines to identify glioma-intrinsic neural pathways that regulate glioma growth. We are also conducting screens in glioma-neuron co-culture, a context in which glioma cell proliferation is greatly increased, to identify compounds that interfere with neuron-glioma communication. These screens identified multiple drug target classes that regulate glioma growth, including certain neurotransmitter receptors and ion channels. Screening hits will be further characterized by genetic knock down of their putative receptors, gene expression analyses, and in vivo testing in orthotopic xenograft models of DMG. Our research is identifying new neural mechanisms in DMG as well as multiple lead compounds acting on different neurophysiological pathways that can be advanced to clinical trials for DMG patients.