New Investigator Grant Awarded to Humsa Venkatesh

Microenvironmental determinants of H3K27M+ diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) progression are incompletely understood. Neuronal activity is emerging as a critical regulator of glioma growth. We recently showed that active neurons exert a mitogenic effect on DIPG through activity-dependent secretion of growth factors, including neuroligin-3 (NLGN3), which acts through recruitment of the PI3K/AKT pathway. ADAM10 was found to be the enzyme mediating the cleavage and secretion of NLGN3, and treatment with an ADAM10 inhibitor significantly slowed tumor growth in mice. We additionally found that NLGN3 facilitates the formation of bona fide AMPA receptor-dependent neuron-glioma synapses. Concordantly, genetic knockdown of an AMPA receptor subunit or pharmacological blockade of glutamatergic signaling slows glioma growth. Together, these findings indicate that both paracrine mechanisms of activity-regulated growth and synaptic integration into neural circuits promotes DIPG progression and elucidate the previously unexplored potential to target neuron-glioma circuit dynamics for therapy of these lethal cancers. This proposal aims to further investigate effective methods to block the complex mechanisms of activity-mediated brain tumor growth and proposes combinatorial dual treatment of DIPG with an ADAM10 inhibitor (INCB7839) together with an AMPA receptor inhibitor (perampanel) to more effectively inhibit neuron-glioma communication. Using molecular biology and neuroscience techniques, we will elucidate the altered downstream oncogenic signaling cascades, the global changes to malignant network activity, the modulation of microenvironmental hyperexcitability, and the changes to malignant neuron:glioma synapse number occurring as an effect of either INCB7839 treatment alone, perampanel treatment alone, or a combination treatment of the two drugs together to target all mechanisms of activity-mediated growth. We will further investigate the effect of this combination treatment strategy on overall DMG/DIPG growth in vivo. By appreciating the crosstalk between neurons and DIPG cells integrating into neural circuitry, this set of proposed studies will answer fundamental questions in this emerging field of the neural regulation of cancers, while potentially changing the way we treat this devastating group of cancers.