Blood-based assays for the detection of glioblastoma RNA biomarkers

 描述（由申请人提供）：胶质瘤约占所有原发性中枢神经系统肿瘤的60%。胶质母细胞瘤（GBM或IV级胶质瘤）占所有胶质瘤的51.2%，是最恶性的形式。在过去的二十年中，GBM治疗的重大突破是将DNA烷化剂替莫唑胺（TMZ）添加到标准治疗中，包括手术和放射治疗，使中位生存期从12.1个月增加到14.6个月;然而，由于生存率低，这些治疗在预防疾病进展方面无效。现在很清楚，GBM患者的一线治疗将根据（表型）遗传亚型变得更加定制。EGFRvIII肽疫苗接种（CDX-110; Rindopepimut）在携带EGFRvIII突变的GBM患者（存在于35%的患者中）的早期临床试验中的有效作用是这种定制治疗的完美例子。中位无进展生存期（PFS）和总生存期（OS）显著高于匹配的历史对照。这些靶向治疗的主要障碍之一是获得易于获得的高质量核酸用于诊断分析。通常，在手术时对切除的GBM肿瘤组织进行EGFRvIII分析，然而，该方法是侵入性的，并且不允许在治疗过程中纵向监测EGFRvIII（和其他生物标志物）。最近，我们的团队已经证明，从GBM患者血液中分离的血小板和细胞外囊泡含有肿瘤衍生的RNA生物标志物，包括EGFRvIII，其与组织活检中的EGFRvIII表达相关。因此，凝血细胞和细胞外囊泡的RNA可以作为生物标志物检测的容易获得的平台，克服了肿瘤异质性和活检分析所观察到的采样误差的问题。在这项提案中，我们将评估血小板和微泡作为一种非侵入性的伴随诊断测试，用于检测胶质母细胞瘤的生物标志物，使用定量分析。此外，我们将使用这些平台纵向监测EGFRvIII状态，从而监测患者对EGFRvIII靶向疫苗的反应。如果成功，这种方法可以广泛应用于正在评估个性化治疗的不同癌症类型。

 DESCRIPTION (provided by applicant): Gliomas account for about 60% of all primary central nervous system tumors. Glioblastoma (GBM or grade IV glioma), which comprises 51.2% of all gliomas, is the most malignant form. Over the last two decades, the major breakthrough in the treatment for GBM has been the addition of the DNA alkylating agent temozolomide (TMZ) to the standard of care including surgery and radiation yielding an increase in the median survival from 12.1 months to 14.6 months; however, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. It is now clear that first-line treatmen for patients with GBM will become more tailored according to (epi)genetic subtypes. The potent effect of EGFRvIII peptide vaccination (CDX-110; Rindopepimut) in early phase clinical trials in patients with GBM harboring EGFRvIII mutation (present in 35% of patients) is a perfect example of such a tailored treatment. Median progression-free survival (PFS) and overall survival (OS) were significantly higher than in matched historical controls. One of the main barriers to these targeted therapies is obtaining easily accessible high-quality nucleic acids for diagnostic analysis. Typically, EGFRvIII profiling is performed at the time of surgery on resected GBM tumor tissues, however, this method is invasive and does not allow monitoring of EGFRvIII (and other biomarkers) longitudinally during the course of therapy. Recently, our team has demonstrated that thrombocytes and extracellular vesicles isolated from blood of GBM patients contain tumor-derived RNA biomarkers, including EGFRvIII, that correlates with EGFRvIII expression in tissue biopsies. Thus, RNA of thrombocytes and extracellular vesicles may serve as a readily accessible platform for biomarker detection, overcoming problems of tumor heterogeneity and sampling error as observed for biopsy analysis. In this proposal, we will evaluate thrombocytes and microvesicles as a non-invasive companion diagnostics test for the detection of glioblastoma biomarkers using quantitative assays. Further, we will use these platforms to monitor EGFRvIII status longitudinally, and thus patient response to EGFRvIII-targeted vaccine. If successful, this method could have a broad application for different cancer types in which personalized therapy is being evaluated.