Blood-based assays for the detection of glioblastoma RNA biomarkers

 描述(申请人提供)：胶质瘤约占所有原发中枢神经系统肿瘤的60%。胶质母细胞瘤(GBM或IV级胶质瘤)是恶性程度最高的肿瘤，占所有胶质瘤的51.2%。在过去的二十年里，治疗GBM的主要突破是在包括手术和放射治疗在内的护理标准中增加了DNA烷化剂替莫唑胺(TMZ)，使中位生存期从12.1个月增加到14.6个月；然而，正如较低的存活率所表明的那样，这些治疗在防止疾病进展方面并不有效。现在很明显，对GBM患者的一线治疗将变得更加根据(EPI)基因亚型量身定做。EGFRvIII多肽疫苗(CDX-110；rindopepimut)在早期临床试验中对携带EGFRvIII突变的GBM患者(存在于35%的患者中)的有效效果就是这种量身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组。这些靶向治疗的主要障碍之一是获得易于获得的用于诊断分析的高质量核酸。通常，EGFRvIII分析是在切除的GBM肿瘤组织手术时进行的，然而，这种方法是侵入性的，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患者的血液中分离的血栓细胞和细胞外小泡含有肿瘤衍生的RNA生物标记物，包括EGFRvIII，它与组织活检中EGFRvIII的表达相关。因此，血栓细胞和细胞外小泡的RNA可以作为生物标志物检测的一个容易获得的平台，克服了活检分析中观察到的肿瘤异质性和采样误差的问题。在这项建议中，我们将评估血栓细胞和微泡作为一种非侵入性的伴随性诊断试验，用于检测胶质母细胞瘤的生物标志物。此外，我们将使用这些平台来纵向监测EGFRvIII状态，从而监测患者对EGFRvIII靶向疫苗的反应。如果成功，这种方法可能会在正在评估个性化治疗的不同癌症类型中得到广泛应用。

 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.