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

基本信息

批准号：
8322111
负责人：
ROBERT Charles SEEGER
金额：
$ 42.67万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
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/8322111
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&apos s Oncology Group Chromogranin A Classification Clinical Clinical Trials Clinical assessments Consolidation Therapy Data Data Analyses Data Set Detection Development Diagnosis Disease Disease Resistance Early treatment Endothelial Cells Enrollment Evaluation Failure Freezing Funding Gene Expression Gene Expression Profile Genes Hematopoietic stem cells Homeobox Individual Isotretinoin MYCN gene Marrow Modeling Mononuclear Myeloablative Chemotherapy Neuroblastoma Normal Cell Outcome Patients Peripheral Blood Stem Cell Primary Neoplasm Recurrence Recurrent disease Reporting Research Design Research Methodology Residual Neoplasm Resistance Risk Sensitivity and Specificity Site Source Specimen Staging Subgroup Survivors TEK gene 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 neuroblastoma cell novel therapeutics prognostic public health relevance research clinical testing response sialogangliosides tool tumor

项目摘要

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/抽象，尽管在过去20年中，对具有高危转移性神经母细胞瘤儿童的治疗显着改善，但只有45％的患者成为长期的无病幸存者，而骨髓是常见的抗性或重复疾病的部位。生存的改善需要开发有效的新疗法，这些新疗法针对患者的生物学风险分层亚组，并开发有效的生物标志物测定法，以评估反应并为长期治疗益处提供替代物。具体目的：1）确定用Taqman（R）低密度阵列（TLDA）测定5个神经母细胞瘤相关基因的骨髓和血液中的“肿瘤负荷”是否可以改善与免疫细胞学学和临床评估相比的响应评估和预测结果。 2）确定骨髓和血液“微环境”基因表达特征是否可以预测结果，并将这些基因与肿瘤负荷数据相结合是否进一步改善了预测的预测。 3）确定对血液和骨髓的TLDA肿瘤负荷/微环境测定法组合数据以及与单独分析相比，来自同一患者的原发性肿瘤的TLDA预测基因表达测定法可以改善结果的预测。研究设计和方法：我们开发了一种新的TLDA测定法，可以同时量化代表正常血液和骨髓细胞的五个神经母细胞瘤基因（“肿瘤负荷”）和38个“微环境”基因。该测定法量化了CHGA，DCX，DDC，PHOX2B和TH的表达，以便可以鉴定出106个正常骨髓或血液单核细胞中的一个肿瘤细胞。初步研究表明，没有免疫细胞学与预后相关的PBSC和骨髓中的“肿瘤负荷”。在一个单独资助的项目中，我们开发了另一种TLDA测定法，该测定法量化了原发性mycn非放大肿瘤中预后的14基因表达特征以预测结果，并且正在为MyCN扩增的肿瘤开发另一个签名。我们应从三个独立的患者中，正在/正在参与了儿童肿瘤学组的六项不同研究中，我们将通过测试3,000个严重冷冻保存的标本（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，在评估反应和预测结果时，将考虑何时获得标本（诊断，诊断和结束时）和治疗（诱导，合并和结合后疗法）的治疗（诱导，巩固和结合后疗法）时的分析。血液和骨髓的肿瘤负荷和微环境数据将与原发性肿瘤的基因表达签名数据相结合，以确定其关系以及提高临床决策结果预测结果的能力。摘要：预计我们对骨髓和血液中神经母细胞瘤细胞的新TLDA分析将改善预测结果，从而为患有高危转移性神经母细胞瘤患者开发更有效的治疗。公共卫生相关性：尽管在过去20年中，针对具有高危转移性神经母细胞瘤的儿童（第4阶段）的儿童的叙述稳步改善，但这些患者中只有45％的患者长期存活，而骨髓是耐药或经常性疾病的常见部位。我们已经开发了一种强大的生物标志物测定法，该测定法通过表达正常的骨髓和血细胞基因来同时量化肿瘤细胞基因和“微环境”的“肿瘤负荷”。我们预计该测定法将成为评估对新治疗策略的反应并预测具有高风险神经母细胞瘤儿童的结果的整体生物标志物工具。