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: 7500654
• 负责人: IZIDORE S LOSSOS
• 金额: $ 27.42万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500654
• 关键词: American Society of Hematology; Antibodies; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Buffers; CHOP protocol-cyclophosphamide/doxorubicin/prednisone/vincristine; Cells; Clinical; Complex; Consensus; Daily; Diagnostic; Diagnostic tests; Diffuse Lymphoma; Disease; Doxorubicin; Endopeptidase K; Facility Construction Funding Category; 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; Numbers; Oligonucleotides; Outcome; Paraffin; Paraffin Embedding; Paraffin Tissue; Pathogenesis; Patients; Polymerase Chain Reaction; Preparation; Process; Proteins; RNA; RNA Degradation; Range; Reporting; Reproducibility; Research; Retrospective Studies; Risk; Sampling; Specimen; Staining method; Stains; Standardization; Standards of Weights and Measures; Structure of germinal center of lymph node; Subgroup; Testing; Time; Tissue Banks; Tissue Microarray; Tissues; Treatment Protocols; Validation; Work; abstracting; base; chemotherapy; clinical application; cohort; design; indexing; large cell Diffuse non-Hodgkin' s lymphoma; novel; novel diagnostics; novel therapeutics; outcome forecast; predictive modeling; prognostic; protein expression; rituximab; sample fixation; 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) 的特点是显着的生物学和临床异质性。在 CHOP 时代，研究表明，DLBCL 患者的生存率可以通过测量有限数量的基因的表达来预测。然而，标准治疗已发展为包括利妥昔单抗联合 CHOP。初步研究表明，添加利妥昔单抗会改变特定分子生物标志物的预测能力，并且与利妥昔单抗抗肿瘤作用相关的新生物标志物可能会变得具有预后意义。因此，迫切需要为接受当前 R-CHOP 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行医方式。此外，之前的所有模型都是基于冷冻标本中的 RNA 测量，其可用性有限，从而限制了所提出的预后模型的适用性。基于广泛可用的石蜡包埋样本，使用 RNA 或免疫组织化学分析基因表达来构建预后模型，将使这些模型在日常临床实践中立即广泛应用。 该项目基于我们实验室开发的从福尔马林固定、石蜡包埋的组织中提取 RNA 的新方法，该方法允许通过实时 PCR 或寡核苷酸微阵列可靠地测量基因表达。该方法将用于实现该项目的目标，包括： 1. 通过基于芯片的基因表达谱分析，确定一系列基因，其表达与接受 R-CHOP 治疗的 DLBCL 患者的生存相关； 2. 基于石蜡标本RNA构建并验证基于石蜡的实时PCR基因表达预后模式； 3. 检查与利妥昔单抗抗肿瘤作用相关的生物标志物对接受 R-CHOP 治疗的 DLBCL 患者的生存预测能力； 4. 根据通过免疫组织化学在蛋白质水平上测量的一组有限基因的表达，构建接受 R-CHOP 治疗的 DLBCL 患者的预后模型。 这些研究应该为最常见类型的淋巴瘤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标的预后能力。预测模型的常规应用将能够识别标准治疗失败的高风险患者，并可能构成 DLBCL 风险调整治疗的基础。此外，对构成预测模型的基因-蛋白质的鉴定将指出DLBCL亚型的独特发病机制，并可能导致新分子治疗靶点的识别。此外，使用新的 RNA 提取方法建立基于石蜡的 RNA 预后模型可以作为其他淋巴瘤和肿瘤的范例。