Development of a Novel Clinical Diagnostic Assay for Peripheral T-cell Lymphoma (PTCL)

项目总结/摘要 外周T细胞淋巴瘤（PTCL）是一种异质性癌症，占所有非霍奇金淋巴瘤的20%。 淋巴瘤（NHL）。世界卫生组织的分类承认了一些不同的亚型， PTCL，但这些不同亚型的诊断是具有挑战性的，即使是专家血液病理学家。 此外，30-50%的PTCL病例根本不能使用当前的方法分类为任何特定的亚型。 诊断方法PTCL患者在当前标准治疗下通常预后不良 在过去的二十年里，PTCL患者的结局没有改善。 然而，靶向特定PTCL亚型的新疗法最近开始测试，其中一些具有 惊人的结果。因此，PTCL及其亚型的准确诊断对于确保 为每位患者选择最合适和最有效的治疗方法。该项目将 利用与淋巴瘤/白血病相关的学术研究人员进行的开创性工作 分子分析项目（LLMPP），其中稳健的分子基因表达（GE）签名已被 鉴定为PTCL的每种主要亚型所特有。该项目将建立在这项工作的基础上，利用它作为 创建用于常规临床应用的商业测定以改善诊断的基础， PTCL患者的治疗和结局。HealthChart LLC是一家最近成立的分子诊断公司， 专注于开发用于癌症和其他疾病的小生境适应症的新型诊断测定法， 已授权与学术工作相关的知识产权和专利组合，是 小企业参与这些研究。第1阶段STTR提案的总体目标是 是将最初开发的“学术性”PTCL诊断和预后GE特征转换为使用 用表达微阵列分析新鲜冷冻标本， 适用于在NanoString nCounter上分析的福尔马林固定石蜡包埋（FFPE）标本 平台本提案的两个目标-目标1。识别一组精简的抄本并创作一部小说 模型能够复制现有的“学术”诊断和预后PTCL签名;目标2. 确认精细化的诊断和预后PTCL基因签名集对患者的适用性。 用于FFPE样本分析的nCounter平台（NanoString）-将创建一个优化的 锁定PTCL签名，建立实验室间重现性的性能规范，并验证 一套严格的目标指标的签名。这些研究将使该测定法能够作为CLIA应用 在第1阶段结束时提供实验室产品，同时将PTCL检测试剂盒定位为过渡到第2阶段开发， 新型和/或现有PTCL的体外诊断（IVD）试剂盒和可能的伴随诊断（CDx） 治疗

Project Summary/Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous cancer that constitutes up to 20% of all non-Hodgkin lymphoma (NHL). The World Health Organization classification recognizes a number of distinct subtypes of PTCL but the diagnosis of these different subtypes is challenging even for expert hematopathologists. Furthermore, 30-50% of PTCL cases are not classifiable into any specific subtype at all using current diagnostic methods. Patients with PTCL generally have a poor prognosis with current standard-of-care therapy, and no improvement in the outcome of PTCL patients has been achieved in the last two decades. However, novel therapies targeted to specific PTCL subtypes have recently begun testing, some with spectacular results. Accurate diagnosis of PTCL and its subtypes has therefore become essential to ensure selection of the most appropriate and effective treatment for each individual patient. This project will leverage seminal work performed by academic investigators associated with the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), in which robust molecular gene expression (GE) signatures have been identified that are unique to each major subtype of PTCL. The project will build upon this work, utilizing it as the basis for the creation of a commercial assay for routine clinical application to improve the diagnosis, treatment, and outcomes of PTCL patients. HealthChart LLC, a recently founded molecular diagnostics firm focused on the development of novel diagnostic assays for niche indications in cancer and other diseases, has licensed the intellectual property and patent portfolio associated with the academic work and is the small business partner in these proposed studies. The overarching goal of this Phase 1 STTR proposal is to transition the “academic” PTCL diagnostic and prognostic GE signatures originally developed using fresh frozen specimens analyzed with expression microarrays to an optimized, locked-down signature applicable to formalin-fixed paraffin-embedded (FFPE) specimens analyzed on the NanoString nCounter platform. The two Aims of this proposal – Aim 1. Identify a reduced set of transcripts and create a novel model able to replicate the existing “academic” diagnostic and prognostic PTCL signature; Aim 2. Confirm the applicability of the refined diagnostic and prognostic PTCL gene signature sets on the nCounter platform (NanoString) for the analysis of FFPE specimens – will create an optimized and locked-down PTCL signature, establish performance specifications for inter-lab reproducibility, and validate the signature to a rigorous set of target metrics. These studies will enable application of the assay as a CLIA lab offering at the end of Phase 1, while positioning the PTCL assay for transition to Phase 2 development as an in vitro diagnostic (IVD) kit and possibly a companion diagnostic (CDx) for novel and/or existing PTCL therapies.