Gene Expression of Neuroblastoma and Normal Cells in Bone Marrow Predicts Outcome

骨髓中神经母细胞瘤和正常细胞的基因表达可预测结果

• 批准号: 7979222
• 负责人: ROBERT Charles SEEGER
• 金额: $ 44.17万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979222
• 关键词: Accounting; Aliquot; Archives; Autologous; B-Lymphocytes; Biological Assay; Biological Markers; Blood; Blood Cells; Blood specimen; Bone Marrow; CD19 gene; Cell Transplants; Cells; Child; Children' s Oncology Group; Chromogranin A; Classification; Clinical; Clinical Trials; Clinical assessments; Consolidation Therapy; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Early treatment; Endothelial Cells; Enrollment; Evaluation; Failure; Freezing; Funding; Gene Expression; Gene Expression Profile; Genes; Hematopoietic stem cells; Homeobox; Individual; Isotretinoin; MYCN gene; Marrow; Methods; Modeling; Monoclonal Antibodies; Mononuclear; Myeloablative Chemotherapy; Neuroblastoma; Normal Cell; Outcome; Patients; Peripheral Blood Stem Cell; Primary Neoplasm; Recurrent disease; Reporting; Research Design; Residual Neoplasm; Resistance; Risk; Sensitivity and Specificity; Site; Source; Specimen; Staging; Subgroup; Survivors; Testing; Time; Tumor Burden; Tyrosine 3-Monooxygenase; abstracting; bone; cell growth; chemotherapy; clinical decision-making; cohort; density; effective therapy; high risk; improved; monocyte; neoplastic cell; novel therapeutics; prognostic; public health relevance; research clinical testing; response; sialogangliosides; tool; tumor

DESCRIPTION (provided by applicant): Project Summary/Abstract Although treatment for children with high-risk metastatic neuroblastoma has improved significantly in the past 20 years, only 45% of these patients become long-term, disease-free survivors, and bone marrow is a frequent site of resistant or recurrent disease. Improvement in survival necessitates development of effective new therapies that target biologically risk-stratified subgroups of patients and also development of effective biomarker assays that assess response and provide surrogates for long-term treatment benefit. Specific Aims: 1) Determine if quantifying "tumor load" in bone marrow and blood with a TaqMan(R) Low Density Array (TLDA) assay for 5 neuroblastoma associated genes improves response evaluation and prediction of outcome compared to immunocytology and clinical evaluations. 2) Determine if bone marrow and blood "microenvironment" gene expression signatures predict outcome and if combining these with tumor load data further improves prediction of outcome. 3) Determine if combining data from the TLDA tumor load/microenvironment assay for blood and marrow and a TLDA predictive gene expression assay for primary tumor from the same patient improves prediction of outcome compared to either assay alone. Research Design and Methods: We developed a new TLDA assay that can simultaneously quantify expression of five neuroblastoma genes ("tumor load") and 38 "microenvironment" genes representing normal blood and marrow cells. This assay quantifies expression of CHGA, DCX, DDC, PHOX2B, and TH so that one tumor cell among 106 normal bone marrow or blood mononuclear cells can be identified. Preliminary studies indicate that "tumor load" in PBSC and bone marrow that does not have detectible tumor cells by immunocytology correlates with outcome. In a separately funded project, we have developed another TLDA assay that quantifies a prognostic 14-gene expression signature in primary MYCN non-amplified tumors to predict outcome, and another signature is being developed for MYCN amplified tumors. We shall extend and validate our preliminary studies by testing 3,000 viably cryopreserved specimens (all have been tested by immunocytology) from three independent cohorts of patients who have been/are being enrolled in six different studies of the Children's Oncology Group. Analysis will take into account when the specimen was obtained (diagnosis and during and at the conclusion of therapy) and treatment (induction, consolidation, and post-consolidation therapies) in evaluating response and predicting outcome compared to immunocytology and standard clinical assessments. Tumor load and microenvironment data for blood and marrow will be combined with gene expression signature data for primary tumors to determine their relationship and their ability to improve prediction of outcome for clinical decision making. Summary: It is anticipated that our new TLDA assay for neuroblastoma cells in marrow and blood will improve prediction of outcome and hence to development of more effective therapy for patients with high-risk metastatic neuroblastoma. PUBLIC HEALTH RELEVANCE: Project Narrative Although treatment has steadily improved in the past 20 years for children with high-risk metastatic neuroblastoma (stage 4), only 45% of these patients survive long-term, and bone marrow is a frequent site of resistant or recurrent disease. We have developed a robust biomarker assay that simultaneously quantifies "tumor load" by expression of tumor cell genes and "microenvironment" by expression of normal marrow and blood cell genes. We anticipate that this assay will become an integral biomarker tool for evaluating response to new therapeutic strategies and for predicting outcome of children with high-risk neuroblastoma.

描述(由申请人提供)：项目摘要/摘要尽管在过去20年中，儿童高危转移性神经母细胞瘤的治疗有了显著改善，但这些患者中只有45%成为长期、无病的幸存者，而且骨髓是耐药或复发疾病的常见部位。为了提高存活率，必须开发针对生物风险分层患者亚群的有效新疗法，并开发有效的生物标记物分析，以评估反应并为长期治疗利益提供替代品。具体目标：1)确定与免疫细胞学和临床评估相比，使用TaqMan(注册商标)低密度阵列(TLDA)分析5个神经母细胞瘤相关基因来量化骨髓和血液中的“肿瘤负荷”是否能改善反应评估和对结果的预测。2)确定骨髓和血液“微环境”基因表达特征是否能预测结果，以及结合肿瘤负荷数据是否能进一步提高对结果的预测。3)确定将血液和骨髓的TLDA肿瘤负荷/微环境分析和同一患者的原发肿瘤的TLDA预测基因表达分析的数据结合起来是否比单独使用任何一种分析方法都能提高对结果的预测。研究设计与方法：我们建立了一种新的TLDA分析方法，可以同时定量5个神经母细胞瘤基因(肿瘤负荷)和38个代表正常血液和骨髓细胞的“微环境”基因的表达。该方法定量检测CHGA、DCX、DDC、PHOX2B和TH的表达，以便在106个正常骨髓或血单个核细胞中鉴定出一个肿瘤细胞。初步研究表明，免疫细胞学检测不到肿瘤细胞的PBSC和骨髓中的“肿瘤负荷”与预后相关。在另一个单独资助的项目中，我们开发了另一种TLDA分析方法，它可以量化MYCN未扩增的原发肿瘤中具有预后意义的14个基因的表达特征，以预测预后，另一种标记正在为MYCN扩增的肿瘤开发。我们将通过测试来自已经/正在参加儿童肿瘤学小组六项不同研究的三个独立队列患者的3000个可活体冷冻保存的样本(均已通过免疫细胞学测试)来扩展和验证我们的初步研究。与免疫细胞学和标准临床评估相比，分析将考虑标本获取的时间(诊断、治疗期间和结束时)和治疗(诱导、巩固和巩固后治疗)，以评估反应和预测结果。血液和骨髓的肿瘤负荷和微环境数据将与原发肿瘤的基因表达特征数据相结合，以确定它们之间的关系及其改善临床决策结果预测的能力。摘要：预计我们新的骨髓和血液中神经母细胞瘤细胞的TLDA分析将改善预后预测，从而为高危转移性神经母细胞瘤患者开发更有效的治疗方法。 公共卫生相关性：项目描述尽管在过去20年中，对高危转移性神经母细胞瘤(4期)儿童的治疗稳步改善，但这些患者中只有45%长期存活，而且骨髓是耐药或复发疾病的常见部位。我们已经开发出一种强大的生物标志物分析方法，它可以同时通过肿瘤细胞基因的表达来量化“肿瘤负荷”，以及通过正常骨髓和血细胞基因的表达来量化“微环境”。我们期望这项检测将成为评估对新治疗策略的反应和预测高危神经母细胞瘤儿童预后的一个完整的生物标志物工具。