Glioma intelligence from behind enemy lines

来自敌后的神经胶质瘤情报

• 批准号: 10566235
• 负责人: Terry Burns
• 金额: $ 54.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566235
• 关键词: Address; Astrocytoma; Biochemical; Biology; Brain; Brain Neoplasms; Catheters; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Cystathionine; DL-alpha-Difluoromethylornithine; Data; Eflornithine; Excision; Feedback; Genetic; Genomics; Glioblastoma; Glioma; Glutathione; Glutathione Disulfide; Human; Image; Implant; In Situ; Intelligence; Investigational Therapies; Knowledge; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methionine Metabolism Pathway; Microdialysis; Modeling; Molecular; Molecular Weight; Monitor; Neurosurgical Procedures; Ornithine; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Pathway interactions; Patients; Pharmacodynamics; Phase; Phenotype; Polyamines; Pre-Clinical Model; Radiation; Recurrence; Reproducibility; Resistance; Safety; Sampling; Sorting; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stress; Stromal Cells; Testing; Therapeutic; Therapeutically Targetable; Time; Tissues; Tumor Escape; Up-Regulation; Xenograft procedure; blood-brain barrier disruption; clinically relevant; cohort; experimental study; extracellular; gain of function; guanidinoacetate; human data; improved outcome; loss of function; metabolome; metabolomics; neurosurgery; novel; novel strategies; pharmacologic; preclinical study; promote resilience; research clinical testing; resilience; stable isotope; standard of care; success; targeted treatment; translational progress; tumor; tumor growth; uptake

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.”

来自敌后的神经胶质瘤情报 分子多样性神经胶质瘤可能利用会聚的代谢存活途径，可以是治疗靶向的。微透析使细胞外微环境的采样，并代表了以前未充分利用的机会，表征和药效学监测活的人胶质瘤，原位。我们从术中获得的胶质瘤微透析液的初步数据显示，癌症弹性的甲硫氨酸相关途径，包括多胺合成的强烈富集。具体而言，迄今为止的结果已经确定胍乙酸（GAA）作为最高度上调的代谢物在胶质瘤微透析液，我们假设结果从上调多胺合成肿瘤内。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可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疗法的早期临床评价期间获得机械反馈。为了研究原位人脑胶质瘤的甲硫氨酸代谢，我们将进行术中微透析和甲硫氨酸示踪，比较微透析液和肿瘤及邻近脑组织的代谢组。切除的组织将用于确定甲硫氨酸相关代谢物的细胞来源。最近的研究表明，不同的肿瘤可以逃避DMFO介导的多胺代谢的上调多胺转运蛋白。已显示用DMFO+AMXT 1501双重阻断多胺合成和多胺转运可改善临床前模型的结果。为了机械地询问多胺代谢，我们将利用微透析进行临床前和临床研究的组合。在0期研究中，在DMFO+AMXT双重给药之前，将患者随机分配至溶媒、DMFO或DMFO+AMXT 1501组，以确定早期治疗应激诱导的细胞外药效学变化。总的来说，这些研究将测试微透析如何用于在活体人脑胶质瘤中进行生化侦察，无论是否有治疗挑战，以获得“来自敌人后方的胶质瘤情报”。