Molecular and Cellular Characterization of Prognostic Immune Response in Childhoo

描述（申请人提供）：室管膜瘤（EPN）是儿科第三大常见脑肿瘤，治疗方法为手术切除和放射治疗。不幸的是，超过50%的EPN患儿会出现肿瘤复发，最终导致死亡。尽管这种疾病很严重，但在确定EPN复发的潜在因素方面进展甚微。我研究的长期目标是通过寻找更有效的EPN预后标志物和阐明EPN生物学信息来解决这一迫切需求，从而促进更有效治疗的发展。我的实验室最近进行的微阵列基因表达研究显示，区分EPN与肿瘤未复发儿童和肿瘤复发儿童的主要特征是免疫反应相关基因的过度表达。这些结果表明，EPN中的宿主抗肿瘤免疫反应，当与标准治疗相结合时，可以完全根除剩余的肿瘤细胞。我的中心假设是，详细描述与EPN良好临床结果相关的免疫相关基因将同时(a)为EPN提供准确的预后标志物，(b)提供人类免疫系统与中枢神经系统肿瘤之间相互作用的关键知识，这将有助于我们理解宿主肿瘤控制。这些方面的任何进展都将有利于儿童EPN的临床试验。我的研究计划的具体目的是：(i)冷冻肿瘤标本的回顾性全局基因和蛋白表达分析，（ii）石蜡包埋和冷冻肿瘤中候选免疫细胞和分子的回顾性组织学分析，（iii）使用新鲜手术样本对肿瘤浸润和周围免疫细胞进行前瞻性分析。这些研究的结果将有可能解决临床问题，即如何识别那些患有EPN的儿童谁将复发，这将使我们更好地关注临床试验的患者选择。除此之外，对于中枢神经系统和其他地方肿瘤的免疫治疗具有更广泛的重要性的是，我们已经在与EPN相关的良好结果中确定了假定的宿主抗肿瘤免疫反应的特征。以前的中枢神经系统肿瘤免疫治疗策略主要基于动物模型的结果，显示出有限的成功。拟议的研究可能通过推进我们对人体如何自然启动和影响针对人类中枢神经系统肿瘤的免疫反应的整体理解来克服这一障碍，而不是以前由此类动物模型提供的近似。这些知识可以用来改善那些有EPN复发可能性的儿童的治疗，并有可能应用于其他中枢神经系统恶性肿瘤。

DESCRIPTION (provided by applicant): Ependymoma (EPN), the third most common brain tumor of pediatrics, is treated by surgical removal and radiation therapy. Unfortunately, more than 50% of children with EPN will suffer from tumor recurrence, which will ultimately result in death. Despite the severity of this disease, little progress has been made in identification of factors underlying EPN recurrence. The long-term goal of my research addresses this urgent need by searching more effective prognostic markers for EPN and elucidating EPN biological information that could facilitate development of more effective therapies. Recent microarray gene expression studies by my laboratory revealed that the predominant feature that distinguishes EPN from children whose tumor did not recur versus those whose did is an overexpression of immune response related genes. These results suggest that a host anti-tumor immune response in EPN, when combined with standard therapy, results in complete eradication of the remaining residual tumor cells. My central hypothesis is that detailed characterization of the immune related genes associated with good clinical outcome in EPN will simultaneously (a) provide an accurate prognostic marker for EPN, and (b) provide critical knowledge of the interaction between the human immune system and CNS tumors that will aid our understanding of host tumor control. Progress on either of these fronts would benefit clinical trials in childhood EPN. The specific aims of my research proposal are (i) retrospective global gene and protein expression analysis of frozen tumor specimens, (ii) retrospective histological analysis of candidate immune cells and molecules in paraffin embedded and frozen tumor, and (iii) prospective analysis of tumor-infiltrating and peripheral immune cells using fresh surgical samples. The results of these studies will potentially solve the clinical problem of how to identify those children with EPN who will recur, which will allow us to better focus patient selection for clinical trials. In addition to this, and with a wider importance to immunotherapy of tumors in the CNS and elsewhere, is the characterization of the putative host anti-tumor immune response that we have identified in good outcome associated EPN. Previous CNS tumor immunotherapeutic strategies, largely based on the results of animal models, have shown limited success. The proposed research may overcome this barrier by advancing our overall understanding of how the body naturally initiates and effects an immune response against CNS tumors in humans, rather than the approximation of this previously afforded by such animal models. This knowledge could then be used to improve therapy for those children with a likelihood of EPN recurrence, with potential application in other CNS malignancies.