Targeting the neuronal microenvironment in glioblastoma

摘要 一组新出现的数据引起了人们对神经系统在糖尿病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，我们自己的团队发现，胶质母细胞瘤可以整合到正常状态 神经回路，神经活动通过直接驱动胶质母细胞瘤的生长和进展 神经元与胶质母细胞瘤细胞之间的谷氨酸能突触及其分泌的旁分泌生长因子 谷氨酸能突触。反过来，胶质母细胞瘤细胞分泌谷氨酸来增加兴奋性和 因此，神经元的活动。这种以谷氨酸为燃料的前馈循环是一种潜在的药物 目标。我们假设以广泛的谷氨酸能信号为靶点来干扰这些神经胶质母细胞瘤 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转导，并减少 胶质母细胞瘤生长。这一假说作出了可用曲利路唑-a进行评估的可检验预测。 神经和神经精神疾病晚期临床试验中的脑渗透药物。 在临床前研究中，我们发现曲利鲁唑降低了胶质母细胞瘤中的谷氨酸。 并提高胶质母细胞瘤小鼠模型的存活率。展望未来，我们的学习计划是 有两个明确的目标。我们建议(目标一)在患者来源的异种异种移植(PDOX)中测试曲利鲁唑。 IDH WT胶质母细胞瘤模型，以及(目标二)进行一项手术机会窗临床试验 曲利鲁唑治疗复发的IDH-WT胶质母细胞瘤。我们将评估曲利卢唑对 临床前模型和手术机会窗试验中胶质母细胞瘤的电生理学研究 术中皮层脑电图以确定曲利鲁唑对神经元过度兴奋性的影响。 将测量异种移植组织和切除的人胶质母细胞瘤中的谷氨酸和药物水平。 组织使用质谱学成像；将使用以下方法进一步评估受试者的谷氨酸水平 围手术期微透析及磁共振波谱成像。我们将检查PDOX组织 并切除人体组织，以寻找神经胶质母细胞瘤信号的生物标志物，包括神经连接蛋白-3的水平 和磷酸化的AMPA受体(胶质母细胞瘤中突触信号的指示物 谷氨酸受体)。我们将评估曲利鲁唑对胶质母细胞瘤在两种GBM PDOX中增殖的影响 模型和切除的人类肿瘤组织中，并将测量临床前模型和 临床试验中的无进展生存。综上所述，这些研究将阐明曲利卢唑对 减少胶质母细胞瘤微环境中的谷氨酸能信号，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了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.