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：用于治疗性临床试验合格性的微卫星不稳定性生物标志物检测 项目摘要 当在临床试验中招募晚期癌症患者时，需要临床级诊断， 检测新型免疫疗法的预测性生物标志物。微卫星不稳定性（MSI）被认为是 癌症免疫治疗的新预测生物标志物。检测MSI目前是通过多个 包括DNA修复途径中四种蛋白质（MLH 1，MSH 2， MSH 6，PMS 2）和PCR，在有限的肿瘤标本上选择五个微卫星位置（2）。这些 诊断测试已经优化用于怀疑具有生殖系Lynch的结直肠癌患者， 综合征不幸的是，这些测定常常耗尽有限的临床样本。next的用法 基于第三代测序（NGS）的检测扩大了分子诊断的范围， 整合MSI检测并消除多个平行检测要求的潜力。而患者 进行其他类型突变（如点突变）的基因组检测，迫切需要 增加目前的分析，包括检测微卫星的不稳定性，因为它的预测价值。此外，委员会认为， 目前的微卫星检测算法是专门为少数癌症类型开发的 因此对于大多数癌症的MSI测试是不准确的。我们的临床实验室改进 符合CLIA修正案的癌症基因组学实验室在开发临床级 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 测序和分析使得能够检测患者标本中的微卫星不稳定性， 不同的癌症类型。在分析验证的UH 2阶段，我们将确定灵敏度， 靶向DNA微卫星测序分析MSI-Dx的特异性、重现性和可报告范围， 利用临床肿瘤标本（目的1）。我们将展示MSI-Dx的可扩展性、快速周转和使用 在一个桌面音序器上在临床确认的UH 3阶段，MSI-Dx检测试剂盒将应用于 包括已知MSI-H肿瘤的不同样本收集，包括结肠直肠、子宫内膜和其他 癌症类型（目标2）。此外，我们将对参加真实的临床肿瘤研究的患者使用MSI-Dx检测试剂盒 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 通过促进针对患有以下疾病的患者的精确医学临床试验， MSI-H肿瘤