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: 9912125
• 负责人: Sameek Roychowdhury
• 金额: $ 31.72万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912125
• 关键词: Advanced Malignant Neoplasm; Algorithms; Bioinformatics; Biological Assay; Biological Markers; Clinical; Clinical Laboratory Improvement Amendments; Clinical Trials; Colorectal; Colorectal Cancer; DNA; DNA Repair Pathway; DNA analysis; DNA sequencing; Detection; Diagnostic; Diagnostic tests; Eligibility Determination; Endometrial; Enrollment; Genomics; Hereditary Nonpolyposis Colorectal Neoplasms; Immunohistochemistry; Immunotherapy; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Microsatellite Instability; Microsatellite Repeats; Molecular Profiling; Mutation; PMS2 gene; Patients; Phase; Point Mutation; Positioning Attribute; Predictive Value; Proteins; Reproducibility; Sensitivity and Specificity; Specimen; Testing; Therapeutic; Therapeutic Clinical Trial; Time; Validation; base; cancer biomarkers; cancer genomics; cancer immunotherapy; cancer type; exhaust; experience; molecular diagnostics; next generation sequencing; novel; novel marker; precision medicine clinical trials; predictive marker; sample collection; tumor

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.

当入学晚期癌症患者参加临床试验时，需要临床级诊断 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 癌症免疫疗法的新型预测生物标志物。目前通过多个检测MSI检测 冗余测定包括在DNA修复途径中四种蛋白质的免疫组织化学（MLH1，MSH2， MSH6，PMS2）和PCR，用于有限肿瘤标本上的五个选定的微卫星位置（2）。这些 诊断测试已针对怀疑有种系的结直肠癌患者进行了优化 综合征。不幸的是，这些测定通常会排气有限的临床标本。下一个使用 基于生成测序（NGS）的测试已扩大了分子诊断的特征，并提高了 潜在地整合MSI检测并消除对多个并行测试的要求。而患者 对其他类型的突变（例如点突变）进行基因组测试，迫切需要 鉴于其预测值，增强当前测定法包括检测微卫星不稳定性。此外， 当前的微卫星检测算法已专门针对少量癌症类型开发 因此，对于大多数癌症而言，对于MSI测试不准确。我们的临床实验室改进 修正案（CLIA） - 合规性癌症基因组学实验室在发展临床等级方面具有丰富的经验 肿瘤测序，生物信息学和突变驱动试验（3-6）。我们假设靶向DNA 测序和分析可以从患者标本中检测微卫星的不稳定性。 多样化的癌症类型。在分析验证的UH2阶段，我们将确定灵敏度 靶向DNA微卫星测序测定的特异性，可重复性和可报告范围，MSI-DX， 利用临床肿瘤标本（AIM 1）。我们将展示可扩展性，快速周转和MSI-DX的使用 在桌面音序器上。在临床验证的UH3阶段，MSI-DX分析将应用于A 由已知的MSI-H肿瘤组成的样品收集的各种集合，包括结直肠癌，子宫内膜和其他 癌症类型（AIM 2）。此外，我们将使用MSI-DX分析用于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 通过促进精密医学临床试验的患者，测定将产生广泛的治疗影响 MSI-H肿瘤。