Glioma intelligence from behind enemy lines

来自敌人后方的胶质瘤情报 分子上不同的胶质瘤可能利用趋同的代谢生存途径，这可能是治疗的靶点。微透析法能够对细胞外微环境进行采样，这是一个以前未被充分利用的机会，可以在原位对活体人脑胶质瘤进行表征和药效学监测。我们从术中获得的胶质瘤微透析液中获得的初步数据显示，蛋氨酸相关的抗癌途径具有很强的富集性，包括多胺合成。具体地说，到目前为止的结果已经确定乙酸胍(GAA)是胶质瘤微透析液中表达最高的代谢物，我们推测这是由于肿瘤内多胺合成上调的结果。这项研究将确定我们的研究结果在更大的胶质瘤队列中的重复性和潜在的治疗意义，询问是否可以利用微透析在候选治疗的早期临床评估中获得机械性反馈。为了原位检测人脑胶质瘤的蛋氨酸代谢，我们将行术中微透析和蛋氨酸示踪，比较微透析液和肿瘤组织及邻近脑组织的代谢组。切除的组织将用于确定蛋氨酸相关代谢物的细胞来源。最近的研究表明，多种肿瘤可以通过上调多胺转运体来逃避DMFO介导的多胺代谢。用DMFO+AMXT 1501双重阻断多胺合成和多胺转运已被证明可以改善临床前模型的结果。为了机械地研究多胺代谢，我们将利用微透析进行一系列临床前和临床研究。在0期研究中，患者将被随机分成Vehicle、DMFO或DMFO+AMXT 1501，然后再双重给予DMFO+AMXT，以确定早期治疗压力引起的细胞外药效学变化。总而言之，这些研究将测试如何在有和没有治疗挑战的情况下，使用微透析在活体人类胶质瘤内进行生化侦察，以获得“来自敌人后方的胶质瘤情报”。

Glioma intelligence from behind enemy lines Molecularly diverse gliomas may leverage convergent metabolic survival pathways that can be therapeutically targetable. Microdialysis enables sampling of the extracellular microenvironment and represents a previously underutilized opportunity to characterize and pharmacodynamically monitor living human gliomas, in situ. Our preliminary data from intraoperatively acquired glioma microdialysate reveal strong enrichment for methionine-associated pathways of cancer resiliency, including polyamine synthesis. Specifically, results to date have identified guanidinoacetate (GAA) as the most highly upregulated metabolite in glioma microdialysate, which we hypothesize results from upregulated polyamine synthesis within the tumor. This study will determine the reproducibility and potential therapeutic implications of our findings across a larger cohort of gliomas, asking if microdialysis could be leveraged to obtain mechanistic feedback during early phase clinical evaluation of candidate therapies. To interrogate methionine metabolism human gliomas in situ, we will perform intra-operative microdialysis and methionine tracing, comparing the metabolome of microdialysate and tissue from tumor and adjacent brain. Resected tissue will be used to determine the cellular source of methionine-associated metabolites. Recent studies have demonstrated that diverse tumors can escape DMFO-mediated polyamine metabolism by upregulation of polyamine transporters. Dual blockade of polyamine synthesis and polyamine transports with  DMFO+AMXT 1501 has been shown to improve outcomes in preclinical models. To mechanistically interrogate polyamine metabolism we will perform a combination of preclinical and clinical studies leveraging microdialysis. In a phase 0 study, patients will be randomized to vehicle, DMFO, or DMFO+AMXT 1501, prior to dual administration of DMFO+AMXT to determine the extracellular pharmacodynamic changes induced by early therapeutic stress. Collectively, these studies will test how microdialysis can be used to perform biochemical reconnaissance within the live human glioma, with and without therapeutic challenge, to gain “glioma intelligence from behind enemy lines.”