Molecular and Cellular Characterization of Prognostic Immune Response in Childhoo

儿童预后免疫反应的分子和细胞特征

• 批准号: 8046331
• 负责人: NICHOLAS K FOREMAN
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-17 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046331
• 关键词: Address; Animal Model; Bioinformatics; Biological; Biometry; Brain Neoplasms; Cells; Central Nervous System Neoplasms; Cessation of life; Child; Childhood; Childhood Brain Neoplasm; Childhood Ependymoma; Children' s Oncology Group; Clinic; Clinical; Clinical Management; Clinical Trials; Collaborations; Collection; Data; Development; Diagnosis; Dimensions; Dissection; Ensure; Ependymoma; Excision; Freezing; Frequencies; Future; Gene Expression; Gene Expression Microarray Analysis; Genes; Goals; Histology; Human; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Investigational Therapies; Knowledge; Laboratories; Little' s Disease; Location; Malignant Neoplasms; Measures; Molecular; Nervous System Trauma; Neuraxis; Operative Surgical Procedures; Outcome; Paraffin Embedding; Patient Selection; Patients; Peripheral; Phenotype; Population; Positioning Attribute; Prognostic Factor; Prognostic Marker; Prospective Studies; Proteins; Proteomics; Radiation therapy; Recurrence; Research; Research Personnel; Research Proposals; Residual Tumors; Retrospective Studies; Role; Sample Size; Sampling; Screening procedure; Series; Severity of illness; Specimen; Testing; Tissue Sample; Tissues; Translating; Two-Dimensional Gel Electrophoresis; Validation; base; design; effective therapy; immune function; improved; neoplastic cell; neuro-oncology; overexpression; peripheral blood; prognostic; prospective; protein expression; public health relevance; response; success; tumor; tumor immunology

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. PUBLIC HEALTH RELEVANCE: Most people with brain tumors die. We have found an immune response in a type of childhood brain tumor called an ependymoma. We wish to explore whether this immune response can be used to cure ependymomas and potentially other brain tumors.

描述（由申请人提供）：室管膜瘤（EPN）是儿科第三种最常见的脑肿瘤，可通过手术切除和放射治疗进行治疗。不幸的是，超过50%的EPN儿童会出现肿瘤复发，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 预后标志物并阐明 EPN 生物学信息来解决这一迫切需求，从而促进更有效疗法的开发。我的实验室最近进行的微阵列基因表达研究表明，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与标准疗法相结合，可以完全根除剩余的残留肿瘤细胞。我的中心假设是，对与 EPN 良好临床结果相关的免疫相关基因的详细表征将同时 (a) 为 EPN 提供准确的预后标记，(b) 提供关于人类免疫系统和 CNS 肿瘤之间相互作用的关键知识这将有助于我们了解宿主肿瘤的控制。这两个方面的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标是（i）冷冻肿瘤标本的回顾性整体基因和蛋白质表达分析，（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，以及（iii）肿瘤的前瞻性分析-使用新鲜的手术样本进行浸润和外周免疫细胞。这些研究的结果将有可能解决如何识别那些会复发的 EPN 儿童的临床问题，这将使我们能够更好地集中临床试验的患者选择。除此之外，对中枢神经系统和其他地方的肿瘤免疫治疗具有更广泛重要性的是我们在与良好结果相关的 EPN 中确定的假定宿主抗肿瘤免疫反应的特征。先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，但取得的成功有限。拟议的研究可以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，而不是像以前通过此类动物模型提供的那样近似。这些知识可用于改善对可能出现 EPN 复发的儿童的治疗，并有可能应用于其他中枢神经系统恶性肿瘤。 公共卫生相关性：大多数患有脑肿瘤的人都会死亡。我们在一种称为室管膜瘤的儿童脑肿瘤中发现了免疫反应。我们希望探索这种免疫反应是否可以用于治疗室管膜瘤和其他潜在的脑肿瘤。