Serum exosome biomarkers for evaluation of glioma drug response

描述(由申请人提供)： 抗击脑癌的进展为“个性化”和改善患者的药物治疗提供了新的机会。这些包括对数百种胶质母细胞瘤(GBM)肿瘤的基因组测序，上调mRNAs的路径分析，针对靶向驱动基因突变的药物设计的日益复杂，以及肿瘤向循环中释放外切体以显示单个肿瘤的基因型别的发现。这项提议将扩大GBM第二阶段药物试验的信息内容，包括一个研究机构，以使用血清外切体中的特定突变和水平的信使核糖核酸和miRNA作为生物标记物，随着时间的推移监测个别患者肿瘤的遗传状态。这些生物标志物有可能阐明肿瘤中的哪些基因变化使患者对特定药物更敏感，治疗期间肿瘤中是否发生代偿性基因变化，以及这些变化如何影响治疗的整体反应。这项临床试验将评估一种新的不可逆的激酶信号通路抑制物，它是由GBM患者的表皮生长因子受体(EGFR)变化激活的。该队列将包括根据肿瘤活检证实有EGFR扩增的复发患者。分子病理学服务将分析一组肿瘤样本中17个癌症驱动基因的基因组DNA突变-同时，我们将从56名患者的纵向血清外切体样本中监测一些对GBM生长至关重要的遗传参数，所有这些患者都将同时进行全面的临床检查。所有样本都将被生物库储存，并具有足够的大小，以便在未来的研究中进行多种额外的分析。将进行统计分析，以评估肿瘤遗传状态与肿瘤体积、无进展存活率和总存活率的放射学评估之间的相关性。我们预测，单个GBM肿瘤的遗传变化星座可以预测它们对特定药物的敏感性，并且可以通过分析循环中的肿瘤外切体的RNA来监测药物治疗的反应。

DESCRIPTION (provided by applicant): Advances in the fight against brain cancer provide new opportunities to "personalize" and improve drug treatment of patients. These have included genome sequencing of hundreds of glioblastoma (GBM) tumors, pathway analysis of upregulated mRNAs, increasing sophistication of drug design to target driver mutations, and the discovery that tumors release exosomes into the circulation that manifest the genotype of individual tumors. This proposal will expand the informational content of a Phase II drug trial for GBM to include a research arm to monitor the genetic status of the tumors in individual patients over time using specific mutations and levels of mRNA and miRNA in serum exosomes as biomarkers. These biomarkers have the potential to elucidate which genetic changes in tumors make patients more responsive to a specific drug, whether compensatory genetic changes occur in the tumor during treatment, and how these influence the overall response to therapy. This clinical trial will evaluate a novel irreversible inhibitor of a kinase signaling pathway which is activated by alterations in the epidermal growth factor receptor (EGFR) in GBM patients. The cohort will consist of recurrent patients with verified EGFR amplification based on tumor biopsies. A subset of tumor samples will be analyzed for mutations in genomic DNA in 17 cancer driver genes by the Molecular Pathology Service - in parallel we will monitor a number of genetic parameters critical for GBM growth in RNA from longitudinal serum exosome samples from 56 patients in this study, all of whom will concurrently have a full clinical workup. All samples will be biobanked and of sufficient size to allow multiple additional assays in future studies. Statistical analysis will be carried out to evaluate correlations between genetic status of tumors and radiographic assessment of tumor volume, progression-free survival and overall survival. We predict that the constellation of genetic changes in individual GBM tumors can predict their susceptibility to specific drugs and that response to drug treatment can be monitored by analysis of RNA from circulating tumor exosomes.