Detection of microsatellite instability biomarkers for therapeutic clinical trial eligibility

检测治疗性临床试验资格的微卫星不稳定性生物标志物

• 批准号: 9313523
• 负责人: Sameek Roychowdhury
• 金额: $ 35.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2018-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313523
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Algorithms; Amendment; Base Pairing; Bioinformatics; Biological Assay; Biological Markers; Cancer Patient; Clinical; Clinical Trials; Colorectal; Colorectal Cancer; Custom; DNA; DNA Mismatch Repair Protein MLH1; DNA Repair; DNA Repair Pathway; DNA analysis; DNA sequencing; Defect; Detection; Development; Diagnostic; Diagnostic tests; Eligibility Determination; Endometrial; Endometrial Carcinoma; Enrollment; Evaluation; Formalin; Freezing; Gene Mutation; Genes; Genomics; Hereditary Nonpolyposis Colorectal Neoplasms; Immune checkpoint inhibitor; Immune system; Immunohistochemistry; Immunotherapy; Inherited; Laboratories; Length; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant neoplasm of thyroid; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair; Molecular; Molecular Profiling; Mutation; Nature; PMS2 gene; Paraffin Embedding; Patient Care; Patients; Performance; Pharmaceutical Preparations; Phase; Point Mutation; Positioning Attribute; Predictive Value; Primary carcinoma of the liver cells; Proteins; Repetitive Sequence; Reproducibility; Retrospective cohort; Running; Sampling; Sensitivity and Specificity; Solid Neoplasm; Specimen; Syndrome; Technology; Testing; Therapeutic; Therapeutic Clinical Trial; Time; Validation; Work; base; cancer genomics; cancer immunotherapy; cancer type; exhaust; exome sequencing; experience; fighting; gene repair; loss of function; malignant stomach neoplasm; molecular diagnostics; next generation sequencing; novel; novel marker; novel therapeutics; precision medicine clinical trials; predictive marker; prospective; sample collection; tumor

Project Title: Detection of microsatellite instability biomarkers for therapeutic clinical trial eligibility Project Summary When enrolling patients with advanced cancer in clinical trials, there is a need for clinical grade diagnostics to detect predictive biomarkers for novel immunotherapies. Microsatellite instability (MSI) has been identified as a novel predictive biomarker for cancer immunotherapy. Detecting MSI is currently accomplished with multiple redundant assays including immunohistochemistry for four proteins in the DNA repair pathway (MLH1, MSH2, MSH6, PMS2) and PCR for five selected microsatellite positions on finite tumor specimens (2). These diagnostic tests have been optimized for patients with colorectal cancer suspected of having germline Lynch Syndrome. Unfortunately, these assays oftentimes exhaust finite clinical specimens. The use of next generation sequencing (NGS)-based tests has expanded the profile of molecular diagnostics and raises the potential to integrate detection of MSI and eliminate the requirement for multiple parallel tests. While patients undergo genomic testing for other types of mutations such as point mutations, there is a critical need to augment current assays to include detection of microsatellite instability given its predictive value. Furthermore, current microsatellite detection algorithms have been specifically developed for a small number of cancer types and therefore are not accurate for MSI testing in most cancers. Our Clinical Laboratory Improvement Amendments (CLIA)--compliant Cancer Genomics Lab has extensive experience in developing clinical grade tumor sequencing, bioinformatics, and mutation-driven trials (3-6). We hypothesize that targeted DNA sequencing and analysis enables the detection of microsatellite instability in patient specimens from diverse cancer types. During the UH2 Phase of Analytic Validation, we will determine the sensitivity, specificity, reproducibility and reportable ranges of a targeted DNA microsatellite sequencing assay, MSI-Dx, utilizing clinical tumor specimens (Aim 1). We will demonstrate scalability, rapid turnaround, and use of MSI-Dx on a desktop sequencer. During the UH3 Phase of Clinical Validation, the MSI-Dx assay will be applied on a diverse collection of samples comprised of known MSI-H tumors including colorectal, endometrial, and other cancer types (Aim 2). Further, we will utilize the MSI-Dx assay for patients enrolled in a real time clinical tumor sequencing study (Aim 3). Importantly, MSI-Dx can be integrated with other NGS-based testing strategies. This assay will have a broad therapeutic impact by facilitating precision medicine clinical trials for patients with MSI-H tumors.

项目名称：检测微卫星不稳定性生物标志物以评估治疗性临床试验资格 项目概要 当晚期癌症患者参加临床试验时，需要临床级诊断来 检测新型免疫疗法的预测生物标志物。微卫星不稳定性（MSI）已被确定为 癌症免疫治疗的新型预测生物标志物。目前检测 MSI 是通过多种方式完成的 冗余检测，包括 DNA 修复途径中四种蛋白（MLH1、MSH2、 MSH6、PMS2) 和 PCR，用于有限肿瘤样本上五个选定的微卫星位置 (2)。这些 针对疑似种系 Lynch 的结直肠癌患者进行了优化诊断测试 综合症。不幸的是，这些测定常常耗尽有限的临床样本。接下来的使用 基于世代测序 (NGS) 的测试扩展了分子诊断的范围并提高了 集成 MSI 检测并消除多个并行测试的要求的潜力。当患者 接受其他类型突变（例如点突变）的基因组测试，迫切需要 考虑到微卫星不稳定性的预测价值，增强了当前的检测方法，包括检测微卫星不稳定性。此外， 目前的微卫星检测算法是专门针对少数癌症类型开发的 因此对于大多数癌症的 MSI 检测并不准确。我们的临床实验室改进 符合修正案（CLIA）的癌症基因组学实验室在开发临床级别方面拥有丰富的经验 肿瘤测序、生物信息学和突变驱动试验 (3-6)。我们假设目标 DNA 测序和分析能够检测患者样本中的微卫星不稳定性 多种癌症类型。在分析验证的 UH2 阶段，我们将确定灵敏度， 靶向 DNA 微卫星测序测定、MSI-Dx 的特异性、重现性和可报告范围， 利用临床肿瘤标本（目标 1）。我们将展示 MSI-Dx 的可扩展性、快速周转和使用 在桌面音序器上。在临床验证的 UH3 阶段，MSI-Dx 检测将应用于 由已知 MSI-H 肿瘤组成的不同样本集合，包括结直肠癌、子宫内膜癌和其他肿瘤 癌症类型（目标 2）。此外，我们将利用 MSI-Dx 检测来招募参加实时临床肿瘤的患者 测序研究（目标 3）。重要的是，MSI-Dx 可以与其他基于 NGS 的测试策略集成。这 检测将通过促进针对患有以下疾病的患者的精准医学临床试验来产生广泛的治疗影响 MSI-H 肿瘤。