Prognostic Models in Diffuse Large B-Cell Lymphoma

弥漫性大 B 细胞淋巴瘤的预后模型

• 批准号: 7880670
• 负责人: IZIDORE S LOSSOS
• 金额: $ 31.87万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880670
• 关键词: American Society of Hematology; Antibodies; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Buffers; Cells; Clinical; Consensus; Cyclophosphamide; Diagnostic; Diagnostic tests; Disease; Doxorubicin; Endopeptidase K; Failure; Fc Receptor; Formalin; Freezing; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Proteins; Genes; Genotype; Goals; Gold; Heterogeneity; Immunoglobulin G; Immunohistochemistry; Institution; International Prognostic Index; Laboratories; Lead; Link; Lymphoid Tissue; Lymphoma; Measurement; Measures; Medicine; Methodology; Methods; Modeling; Molecular; Molecular Profiling; Monitor; Monoclonal Antibodies; Non-Hodgkin' s Lymphoma; Oligonucleotides; Outcome; Paraffin; Paraffin Embedding; Paraffin Tissue; Pathogenesis; Patients; Prednisone; Preparation; Process; Proteins; RNA; RNA Degradation; Regimen; Reporting; Reproducibility; Research; Retrospective Studies; Risk; Sampling; Specimen; Staining method; Stains; Standardization; Structure of germinal center of lymph node; Subgroup; Testing; Time; Tissue Banking; Tissue Banks; Tissue Microarray; Tissues; Validation; Vincristine; Work; abstracting; base; chemotherapy; clinical application; clinical practice; cohort; design; high risk; indexing; large cell Diffuse non-Hodgkin' s lymphoma; meetings; new therapeutic target; novel; novel diagnostics; outcome forecast; predictive modeling; prognostic; protein complex; protein expression; rituximab; sample fixation; standard care; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) is characterized by marked biological and clinical heterogeneity. In the CHOP-era, it was demonstrated that survival of DLBCL patients can be predicted by measurement of expression of a limited number of genes. However, the standard treatment has evolved to include the rituximab with CHOP. Initial studies suggest that addition of rituximab changes the predictive power of specific molecular biomarkers and it is possible that new biomarkers associated with the anti-tumor effects of rituximab may become prognostically significant. Therefore, there is an urgent need to establish reliable biomarker-based prognostic models for DLBCL patients treated with the current standard regimen of R-CHOP, which will potentially change the way we practice medicine. In addition, all the previous models were based on RNA measurement in frozen specimens, which availability is limited thus restricting applicability of the proposed prognostic models. Construction of prognostic models based on widely available paraffin embedded samples using either RNA or immunohistochemistry for analysis of gene expression would allow immediate and widespread applicability of these models in daily clinical practice. This project is based on a new methodology of RNA extraction from formalin-fixed, paraffin-embedded tissues, developed in our laboratory, which allows reliable measurement of gene expression by either real-time PCR or oligo-microarrays. This methodology will be used to accomplish the goals of this project that include: 1. Identify a list of genes which expression correlates with survival of DLBCL patients treated with R-CHOP by array-based gene expression profiling; 2. Construct and validate a paraffin-based real-time PCR gene expression prognostic mode based on RNA derived from paraffin specimens; 3. Examine the survival predictive power of biomarkers associated with the anti-tumor effects of rituximab in DLBCL patients treated with R-CHOP; 4. Construct a prognostic model for DLBCL patients treated with R-CHOP based on the expression of a limited set of genes measured at the protein level by immunohistochemistry. These studies should define paraffin-based molecular prognostic models for most common type of lymphoma that will be used in clinical practice and will add to the prognostic power of the current clinical prognostic indexes. Routine application of the prediction models will enable identification of patients at high risk for standard therapy failure and may form the basis for risk-adjusted therapies for DLBCL. Furthermore, identification of genes-proteins comprising the predictive models will point to distinct pathogenesis mechanisms of DLBCL subtypes and potentially lead to recognition of new molecular therapeutic targets. Further, establishment of a paraffin-based RNA prognostic model using the new methodology of RNA extraction could serve as a paradigm for other lymphomas and tumors.

描述（由申请人提供）：弥漫性大B细胞淋巴瘤（DLBCL）的特征是生物学和临床异质性。在Chop-era中，证明DLBCL患者的存活可以通过测量有限数量的基因的表达来预测。但是，标准治疗已演变为包括用切碎的利妥昔单抗。最初的研究表明，利妥昔单抗的添加改变了特定分子生物标志物的预测能力，与利妥昔单抗的抗肿瘤作用相关的新生物标志物可能在预后具有显着意义。因此，迫切需要为使用R-Chop的当前标准方案治疗的DLBCL患者建立可靠的基于生物标志物的预后模型，这可能会改变我们的医学方式。此外，所有先前的模型均基于冷冻标本中的RNA测量，其可用性受到限制，从而限制了所提出的预后模型的适用性。使用RNA或免疫组织化学分析基因表达的基于广泛可用的石蜡嵌入样品的预后模型将允许这些模型在日常临床实践中立即和广泛适用。 该项目基于在我们的实验室中开发的福尔马林固定，石蜡包裹的组织中RNA提取的新方法，该组织允许通过实时PCR或Oligo-Microars可靠地测量基因表达。该方法将用于实现该项目的目标，该项目包括：1。确定与通过基于阵列的基因表达分析治疗的DLBCL患者生存相关的基因列表； 2。构建和验证基于石蜡标本的RNA的基于石蜡的实时PCR基因表达预后模式； 3。检查与利妥昔单抗在用R-Chop治疗的DLBCL患者中，生物标志物与抗肿瘤作用相关的生存预测能力； 4.基于通过免疫组织化学在蛋白质水平上测得的有限基因的表达，构建了用R-CHOP治疗的DLBCL患者的预后模型。 这些研究应为最常见的淋巴瘤类型定义基于石蜡的分子预后模型，该模型将用于临床实践，并将增加当前临床预后指数的预后能力。预测模型的常规应用将使标准治疗失败的高风险患者识别，并可能构成DLBCL风险调整疗法的基础。此外，包括预测模型的基因蛋白的鉴定将指出DLBCL亚型的不同发病机理，并有可能导致识别新分子治疗靶标。此外，使用新的RNA提取方法来建立基于石蜡的RNA预后模型，可以作为其他淋巴瘤和肿瘤的范例。