Development of Mantle Cell Lymphoma Proliferation Signature Assay

套细胞淋巴瘤增殖特征检测的发展

• 批准号: 9535251
• 负责人: Lisa Rimsza
• 金额: $ 19.86万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535251
• 关键词: Adopted; Age; American; American Society of Clinical Oncology; Arizona; Attention; B lymphoid malignancy; Behavior; Biological; Biological Assay; Biological Markers; Biopsy; CLIA certified; Cell Count; Cell Cycle; Cell Proliferation; Chicago; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Clinical Trials Design; Cyclin D1; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diagnostic Specificity; Disease; Eastern Cooperative Oncology Group; Evaluation; FDA approved; Formalin; Freezing; Gene Expression Profiling; Genes; Goals; High Dose Chemotherapy; Immune system; Immunohistochemistry; Indolent; Ki-67 Antigen; Laboratories; Lead; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Methods; Molecular; Molecular Profiling; National Cancer Institute; Nuclear; Oral; Paraffin Embedding; Pathologic; Pathologist; Patient observation; Patient risk; Patients; Pharmacologic Substance; Phase; Physicians; Population; Precision therapeutics; Predictive Value; Principal Investigator; Procedures; Process; Progression-Free Survivals; Proteins; Recommendation; Regimen; Reproducibility; Research; Risk; Risk stratification; Sensitivity and Specificity; Southwest Oncology Group; Standardization; Stem cell transplant; System; Techniques; Testing; Therapeutic; Tissue Embedding; Tissues; Validation; Variant; Work; assay development; base; biomarker development; clinical application; clinical diagnostics; clinical practice; clinical risk; cohort; college; digital; high risk; improved; leukemia/lymphoma; malignant breast neoplasm; molecular diagnostics; nano-string; novel; older patient; overexpression; prognostic; prognostic assays; prognostic value; programs; prospective; t(11; 14)(q13; q32)

PROJECT SUMMARY/ABSTRACT This proposal, “Assay Development of the MCL35 for Mantle Cell Lymphoma (MCL),” is written to validate a prognostic assay for MCL based on quantification of a proliferation signature using digital gene expression analysis. MCL is a B cell malignancy with a broad spectrum of clinical, pathological and biological features. MCL is defined by the t(11;14)(q13;q32) translocation, which results in over expression of the cyclin D1 protein and cell cycle dysregulation. MCL cases have markedly variable clinical behavior ranging from indolent to highly aggressive disease, with treatment options ranging from watchful waiting to high dose chemotherapy and stem cell transplant. The current approach to treatment is based largely on the patient's age at diagnosis and currently there is no therapeutic standard. Previously, our research consortium, the Lymphoma and Leukemia Molecular Profiling Project (LLMPP) analyzed snap frozen MCL tissue biopsies using gene expression profiling (GEP) and identified a “Proliferation Signature” as the most powerful biomarker correlating with patient survival in MCL. However, the original techniques using frozen tissues and GEP were impractical for routine diagnostics. A potentially easy solution has been to use immunohistochemistry on tissue biopsies to assess the presence of the Ki67 antigen as a global marker of cell proliferation. Ki67 studies have been prognostic in multiple studies using various thresholds; however, there are serious issues with reproducibility between different lab techniques and Pathologists' approach to interpretation. Therefore, as part of our work in the National Cancer Institute's SPECSII program, we developed a novel GEP proliferation signature assay for MCL that works well in formalin-fixed, paraffin-embedded tissues (FFPET) called the “MCL35”. The MCL35 uses the clinical-grade NanoString nCounter system, which is FDA-approved as the technical platform for the ProSigna Breast Cancer assay. The MCL35 is accurate, reproducible, with an inter-lab reproducibility of 100% in our initial work, making it a strong candidate for application in the clinical diagnostic setting. The MCL35 assay has gained attention since first being orally presented at the American Society of Clinical Oncology in June 2016, and we are in discussions with pharmaceutical companies and clinical trial cooperative groups on applications for the assay. The goals of the current project are first to thoroughly analytically validate the MCL35 (UH2 phase); then, use the refined assay to retrospectively interrogate clinical trial cohorts to establish it's clinical validity (UH3 phase). The long term goal is to use the resulting refined and validated MCL35 to prospectively identify those MCL patients in need of immediate curative intent therapy in order to design clinical trials around this high risk subset and improve patient survival.

项目概要/摘要 该提案“套细胞淋巴瘤 (MCL) 的 MCL35 检测开发”旨在验证 基于使用数字基因表达对增殖特征进行量化的 MCL 预后分析 MCL 是一种 B 细胞恶性肿瘤，具有广泛的临床、病理和生物学特征。 MCL 由 t(11;14)(q13;q32) 易位定义，导致细胞周期蛋白 D1 蛋白过度表达 MCL 病例的临床行为存在显着差异，从惰性到惰性。 高度侵袭性的疾病，治疗选择范围从观察等待到高剂量化疗 目前的治疗方法主要取决于患者诊断时的年龄。 目前还没有治疗标准，我们的研究联盟、淋巴瘤和 白血病分子谱分析项目 (LLMPP) 使用基因分析速冻 MCL 组织活检 表达谱 (GEP) 并确定“增殖特征”作为最强大的相关生物标志物 然而，最初使用冷冻组织和 GEP 的技术是不切实际的。 对于常规诊断，一个可能简单的解决方案是对组织活检使用免疫组织化学。 评估 Ki67 抗原的存在作为细胞增殖的总体标记已进行了研究。 使用不同阈值的多项研究的预后，存在严重的重现性问题； 因此，作为我们工作的一部分，不同的实验室技术和病理学家的解释方法之间存在差异。 在国家癌症研究所的 SPECSII 项目中，我们开发了一种新型 GEP 增殖特征测定法，用于 在福尔马林固定石蜡包埋组织 (FFPET) 中效果良好的 MCL，称为“MCL35”。 使用经 FDA 批准的临床级 NanoString nCounter 系统作为技术平台 ProSigna 乳腺癌检测准确、重复性好，实验室间重复性达 100%。 在我们的初步工作中，使其成为临床诊断环境中应用的有力候选者。 自从首次在美国临床肿瘤学会口头提出以来，检测方法就引起了人们的关注。 2016年6月，正在与药企、临床试验合作组洽谈 当前项目的目标首先是彻底分析验证。 MCL35（UH2期）；然后，使用细化的回顾性询问临床测定试验队列来建立 它的临床有效性（UH3 阶段）是使用由此产生的精炼和验证的 MCL35。 前瞻性地识别那些需要立即治疗的 MCL 患者，以便设计 围绕这一高风险子集进行临床试验并提高患者的生存率。