The Impact of Local and Reversible Change to GABAergic Inhibitory Signaling on Tumor-Induced Cortical Dysfunction in Glioma

PROJECT SUMMARY Tumor-associated seizures and focal neurological deficits are a major source of morbidity in patients with diffusely infiltrating glioma. Tumor-associated seizures are difficult to treat, and patients with diffusely infiltrating glioma often experience recurrent seizures despite treatment with multiple anticonvulsant drugs. Tumor-induced neurological deficits can be equally debilitating and are associated with decreased quality of life, reduced functional independence, and decreased survival. Thus, targeted therapy to address these symptoms is of great clinical significance and remains an unmet need in patients with diffusely infiltrating glioma. Using a mouse model of tumor-associated seizures, we showed that cortical hyper-excitability and seizures are associated with loss of inhibitory GABAergic signaling. Our published work and preliminary data demonstrate that acute treatment with the mTOR inhibitor AZD8055 1. Reduces tumor-associated seizures 2. Restores normal excitatory neuron stimulus-triggered responses to physiologic stimulation in a model of tumor-induced neurological deficits. and 3. Restores local inhibitory GABAergic signaling - through its effects on GABAergic interneuron firing and the GABA-A reversal potential of excitatory neurons - thereby providing a potential mechanism for its anticonvulsant effects and pointing to potential synergistic effects of combining AZD8055 with GABAergic drugs as a new therapeutic strategy. Here we propose to mechanistically link and leverage these inter-related findings and test the hypothesis that tumor-induced alterations in peritumoral neuronal mTOR and GABAergic signaling mechanistically contribute to both tumor-associated seizures and focal neurological deficits and thus represent synergistic targets for tumor-induced neurological dysfunction. We will test this in 3 aims: In Aim 1, we will test whether mTOR-dependent alterations in GABAergic signaling are necessary to decrease tumor-associated seizures. In this aim we will also use systemic and local delivery to test the anticonvulsant effects of AZD8055 and the GABA transaminase inhibitor vigabatrin. In Aim 2, we will test whether mTOR-dependent alterations in GABAergic signaling are necessary to restore local cortical function and restore neurological deficits. In Aim 3, we will determine the effect of mTOR inhibition on the electrophysiologic properties and expression profiles of peritumoral neurons in human glioma.