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: 9981868
• 负责人: Lisa Rimsza
• 金额: $ 33.38万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981868
• 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; 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; 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.

项目摘要/摘要 该提议是“针对地幔细胞淋巴瘤（MCL）的MCL35的测定开发”，以验证A 使用数字基因表达的增殖签名的数量，对MCL的预后测定 分析。 MCL是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，这导致细胞周期蛋白D1蛋白的表达过度表达 和细胞周期失调。 MCL病例的临床行为明显变化。 高度侵略性疾病，治疗方案范围从观察等待到高剂量化学疗法 和干细胞移植。当前的治疗方法主要基于患者的诊断年龄 目前尚无治疗标准。以前，我们的研究联盟，淋巴瘤和 白血病分子分析项目（LLMPP）使用基因分析了SNAP冷冻MCL组织活检 表达谱分析（GEP）并确定“扩散签名”是最强大的生物标志物 患者在MCL中存活。但是，使用冷冻组织和GEP的原始技术是不切实际的 用于常规诊断。一种潜在的简单解决方案是在组织活检中使用免疫组织化学 评估Ki67抗原作为细胞增殖的全球标志物的存在。 KI67研究已经 在使用各种阈值的多项研究中进行预后；但是，可重复性存在严重的问题 在不同的实验室技术和病理学家的解释方法之间。因此，作为我们工作的一部分 国家癌症研究所的SpecSII计划，我们开发了一种新颖的GEP扩散签名测定法 在福尔马林固定的，石蜡包裹的组织（FFPET）中效果很好的MCL称为“ Mcl35”。 Mcl35 使用临床级纳米串NCounter系统，该系统被FDA批准为技术平台 Prosigna乳腺癌测定法。 MCL35是准确的，可再现的，LAB间可重复性为100％ 在我们的最初工作中，使其成为在临床诊断环境中应用的有力候选人。 Mcl35 自从首次口头出现在美国临床肿瘤学会以来，测定已引起人们的关注。 2016年6月，我们正在与制药公司和临床试验合作小组讨论 测定的申请。当前项目的目标是首先在分析上彻底验证 Mcl35（UH2相）;然后，使用精致的测定进行回顾性询问临床试验队列以建立 它是临床有效性（UH3阶段）。长期目标是将所得的精制和验证的MCL35用于 前瞻性识别需要立即治愈意图治疗的MCL患者以设计 围绕该高风险子集的临床试验并改善患者的生存率。