Experimental Therapeutics and BioMonitoring for Brain Tumors

描述（由申请人提供）：本提案的目的是通过增强溶瘤治疗来改善神经胶质瘤的治疗，并开发血清微泡作为个体GBM肿瘤的遗传和表型特性及其对治疗的反应的生物标志物。项目1（Chiocca/Kaur）将评估HSV感染的胶质瘤细胞产生的微泡中的病毒RNA是否增加肿瘤对溶瘤的易感性，并评估肿瘤来源的血清微泡中的病毒和细胞mRNA作为溶瘤治疗的生物标志物。项目2（Weissleder/Hahko）将应用基于纳米技术的诊断磁共振（DMR）来表征血清中的微囊泡数量和抗原谱，这些微囊泡数量和抗原谱基于对肿瘤发生至关重要的蛋白质，使用来自患有胶质母细胞瘤（GBM）并接受不同治疗模式的小鼠和患者的血清。项目3（Breakefield）将使用抗体捕获微流控室表征和富集肿瘤来源的微泡血清，并使用项目2中的血清样品表征和富集GBM相关RNA中的数量水平和突变。这些项目将得到以下方面的支持：核心A核心B（Carter）维持来自接受标准治疗或临床I/II期试验的患者的人GBM肿瘤和纵向血清样品的生物储存库，向项目2和3提供去识别样品，并与临床参数进行生物统计学关联;和Core C（Charest），以向项目1提供具有代表人GBM的两种亚型中的驱动突变的突变的基因工程GBM小鼠，并向项目2和3提供去识别的肿瘤/血清样品和与肿瘤体积和存活时间的生物统计学相关性。该项目将开发和评估新的可获得的血清生物标志物，以促进在小鼠模型和人类患者中评估治疗范例，包括对治疗的真实的时间响应和对治疗的抗性机制。

DESCRIPTION (provided by applicant): The goals of this proposal are to improve treatment for gliomas by enhancement of oncolytic therapy and to develop serum microvesicles as biomarkers for genetic and phenotypic properties of individual GBM tumors and their response to therapy. Project 1 (Chiocca/Kaur) will evaluate whether viral RNA in microvesicles produced by HSV-infected glioma cells increases susceptibility of tumors to oncolysis, and assess viral and cellular mRNAs in tumor-derived serum microvesicles as biomarkers of oncolytic therapy. Project 2 (Weissleder/Hahko) will apply nanotechnology-based diagnostic magnetic resonance (DMR) to characterize micro vesicle number and antigenic profiles in serum based on proteins critical to oncogenesis using serum from mice and patients bearing glioblastoma (GBM) and undergoing different treatment paradigms. Project 3 (Breakefield) will characterize and enrich tumor-derived microvesicles serum using antibody-capture microfluidic chambers and quantities levels and mutations in GBM-related RNAs using serum samples as in Project 2. These projects will be supported by: Core A (Hochberg) to provide oversight for programmatic organization and neuropathology; Core B (Carter) to maintain a biorepository of human GBM tumor and longitudinal serum samples from patients undergoing standard-of-care therapy or clinical Phase l/ll trials, to supply de-identified samples to Project 2 and 3, and to carry out biostatistical correlations with clinical parameters; and Core C (Charest) to provide genetically engineered GBM mice with mutations representing driver mutations in two subtypes of human GBMs to Project 1, and de-identified tumor/serum samples and biostatistical correlations with tumor volume and survival time to Projects 2 and 3. This program will develop and evaluate new accessible serum biomarkers to facilitate evaluation of therapeutic paradigms in mouse models and human patients both in terms of real time response to therapy and mechanisms of resistance to therapy.