Targeting the neuronal microenvironment in glioblastoma

总结 一组新的数据引起了人们对神经系统在脑梗死发病机制中的中心作用的关注。 胶质母细胞瘤在初步研究中，我们自己的小组发现，胶质母细胞瘤整合到正常细胞中， 神经回路，并且神经元活动通过直接的神经传导驱动胶质母细胞瘤的生长和进展。 神经元和胶质母细胞瘤细胞之间的神经元能突触和由神经元分泌的旁分泌生长因子 神经元突触。反过来，胶质母细胞瘤细胞分泌谷氨酸来增加兴奋性， 从而影响神经元的活动。这种以谷氨酸为燃料的前向喂养循环提供了一种潜在的药物 目标我们假设，广泛靶向胶质母细胞瘤的神经元信号传导， 相互作用将降低神经元的过度兴奋性，减少神经元到胶质母细胞瘤的信号传导， 胶质母细胞瘤生长。这一假设作出了可检验的预测，可以使用曲立鲁唑- a 脑渗透药物在神经和神经精神疾病的晚期临床试验中。 在临床前研究中，我们发现曲立鲁唑减少胶质母细胞瘤中的谷氨酸， 在胶质母细胞瘤的鼠模型中，展望未来，我们的学习计划 两个具体目标。我们提出（目的一）在患者源性原位异种移植（PDOX）中测试曲立鲁唑 IDH WT胶质母细胞瘤模型，并（目的二）进行手术机会窗口的临床试验， 曲立鲁唑在患有复发性IDH WT胶质母细胞瘤的成人受试者中的应用。我们将评估曲立鲁唑对 胶质母细胞瘤电生理学在临床前模型和手术机会窗试验中使用 术中皮质电描记术，以确定曲立鲁唑对神经元过度兴奋的影响。 将在异种移植组织和切除的人胶质母细胞瘤中测量谷氨酸盐和药物水平 组织使用质谱成像;谷氨酸水平将进一步评估人类受试者使用 围手术期微透析和磁共振光谱成像。我们会检查PDOX组织 以及切除的人类组织中神经胶质母细胞瘤信号传导的生物标志物，包括神经配素-3水平 和磷酸化AMPA受体（胶质母细胞瘤中通过一种亚型的 谷氨酸受体）。我们将评估曲立鲁唑对GBM PDOX和GBM PDOX中胶质母细胞瘤增殖的影响。 在临床前模型和切除的人肿瘤组织中，将测量总生存期， 临床试验中的无进展生存率。总之，这些研究将阐明曲立鲁唑对 减少胶质母细胞瘤微环境中的神经元能信号传导，并破坏这些致病神经元， 胶质母细胞瘤的相互作用，有力地促进胶质母细胞瘤的进展。

Summary An emerging body of data draws attention to the central role of the nervous system in pathogenesis of glioblastoma. In preliminary studies our own group has discovered that glioblastoma integrates into normal neural circuits, and that neuronal activity drives glioblastoma growth and progression through direct glutamatergic synapses between neurons and glioblastoma cells and by paracrine growth factors secreted by glutamatergic synapses. In turn, glioblastoma cells secrete glutamate to increase the excitability and consequently the activity of neurons. This glutamate-fueled, forward-feeding cycle presents a potential drug target. We hypothesize that targeting glutamatergic signaling broadly to disrupt these neuron – glioblastoma interactions will decrease neuronal hyperexcitability, decrease neuron-to-glioblastoma signaling and decrease glioblastoma growth. This hypothesis makes testable predictions that can be assessed using troriluzole – a brain penetrant drug in advanced phase clinical trials for neurological and neuropsychiatric diseases. In preclinical studies, we find that troriluzole decreases glutamate in the glioblastoma microenvironment and increases survival in a murine model of glioblastoma. Going forward, our study plan has two specific aims. We propose (Aim one) to test troriluzole in patient-derived orthotopic xenograft (PDOX) models of IDH WT glioblastoma, and (Aim two) to conduct a surgical window-of-opportunity clinical trial of troriluzole in adult subjects with recurrent IDH WT glioblastoma. We will assess effects of troriluzole on glioblastoma electrophysiology in both preclinical models and in the surgical window-of-opportunity trial using intraoperative electrocorticography to determine the effects of troriluzole on neuronal hyperexcitability. Glutamate and drug levels will be measured in both xenograft tissue and in resected human glioblastoma tissue using mass spectrometry imaging; glutamate levels will be further assessed in human subjects using perioperative microdialysis and magnetic resonance spectrometry imaging. We will examine the PDOX tissue and resected human tissue for biomarkers of neuron-glioblastoma signaling, including levels of neuroligin-3 and phosphorylated AMPA receptors (an indicator of synaptic signaling in glioblastoma through a subtype of glutamate receptor). We will assess effects of troriluzole on glioblastoma proliferation in both GBM PDOX models and in resected human tumor tissue, and will measure overall survival in the preclinical models and progression-free survival in the clinical trial. Together, these studies will elucidate the efficacy of troriluzole to decrease glutamatergic signaling in the glioblastoma microenvironment and disrupt these pathogenic neuron- glioblastoma interactions that robustly promote glioblastoma progression.