Liquid Biopsy for Rapid Detection and Real Time Monitoring of FGFR-altered Cancers

液体活检用于快速检测和实时监测 FGFR 改变的癌症

• 批准号: 10282372
• 负责人: Sameek Roychowdhury
• 金额: $ 24.24万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282372
• 关键词: Address; Advanced Malignant Neoplasm; Autopsy; Bioinformatics; Biological Assay; Blood Tests; Blood specimen; Cancer Patient; Cell Line; Cholangiocarcinoma; Clinical; Clinical Laboratory Improvement Amendments; Clinical Trials; Complex; Coupling; DNA Sequence Alteration; DNA sequencing; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disseminated Malignant Neoplasm; Drug resistance; Early Diagnosis; Enrollment; Evaluation; Exclusion; FDA approved; FGFR1 gene; FGFR2 gene; Fibroblast Growth Factor Receptors; Gene Fusion; Genes; Genomic Segment; Grant; Growth Factor Receptor Genes; Heterogeneity; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methods; Monitor; Mutation; Nature; Ohio; Patient Care; Patients; Performance; Prognosis; Progression-Free Survivals; ROS1 gene; Rapid diagnostics; Reproducibility; Research; Resistance; Resistance development; Retrospective cohort; Sampling; Selection for Treatments; Sensitivity and Specificity; Single Nucleotide Polymorphism; Site; Solid Neoplasm; Technology; Testing; Time; Tumor Burden; Tumor Tissue; Universities; Urothelium; Validation; X-Ray Computed Tomography; assay development; base; cancer genomics; cell free DNA; cohort; cost; cost effective; design; detection limit; expedited review; experience; improved; inhibitor/antagonist; kinase inhibitor; liquid biopsy; molecular diagnostics; novel; novel strategies; novel therapeutics; patient screening; prospective; rapid detection; rapid diagnosis; real time monitoring; resistance mutation; response; synthetic construct; targeted treatment; therapy development; time use; tool; treatment response; tumor; validation studies; variant detection; virtual

Liquid Biopsy for Rapid Detection and Real Time Monitoring of FGFR-altered Cancers Patients with advanced cancers driven by fibroblast growth factor receptor (FGFR) alterations, including gene fusions and single nucleotide variants (SNVs), are benefiting from several new FGFR kinase inhibitors. Erdafitinib and pemigatinib were recently FDA approved for bladder cancer and cholangiocarcinoma, respectively, and other FGFR inhibitors have received fast-track designation and are being explored in tumor agnostic basket trials. Patients are experiencing improved overall survival and progression free survival, with high overall response rates. Unfortunately, virtually all patients eventually develop resistance to these inhibitors, oftentimes through acquisition of secondary FGFR mutations. FGFR inhibitor development is hindered by the lack of accurate and comprehensive methods to 1) rapidly detect FGFR alterations in order to qualify patients for clinical trials, 2) monitor therapeutic response, and 3) characterize emerging drug resistance. The development of novel testing strategies, such as non-invasive liquid biopsies, can fulfill these unmet needs for diagnosis, prognosis, and therapy selection. Liquid biopsies evaluate a blood sample, from which cell-free DNA (cfDNA) shed by the tumor is sequenced to detect genomic alterations. The technical specifications for existing commercial cfDNA tests show that these assays are not validated for FGFR fusions and have insufficient sensitivities of ~30% for FGFR fusions. Additionally, commercial tests are too large and costly to repeat frequently for therapy and disease monitoring. Thus, we propose to develop and validate an FGFR-focused, accurate, and cost-effective cfDNA sequencing assay (FGFR-Dx) for real-time testing to support rapid detection, response monitoring, and early detection of resistance. Our team at Ohio State University has six active FGFR inhibitor clinical trials, a large cohort of FGFR true positives, and a Clinical Laboratory Improvement Amendments (CLIA)-compliant Cancer Genomics Lab with extensive experience performing clinical-grade tumor sequencing and bioinformatics analysis for detection and interpretation of gene fusions and single nucleotide variants. Further, we have paired this cfDNA development with a rapid research autopsy study that will enable the first systematic evaluation of detection limits for cfDNA by assessing how accurately the heterogeneity observed across tumor samples from multiple sites is represented in cfDNA. We propose the following Aims to address the criteria for PAR-18-317: 1) Analytically validate a targeted liquid biopsy assay (FGFR-Dx) to detect fusions and single nucleotide variants (SNVs) in FGFR1-3; 2) Establish the clinical validity of FGFR-Dx to detect FGFR fusions and SNVs. In summary, coupling the development of an FGFR-focused liquid biopsy with rapid research autopsy can broadly impact the field’s understanding and application of cfDNA approaches in patients with FGFR-altered and other cancers.

液体活检用于FGFR基因突变癌的快速检测和实时监测 成纤维细胞生长因子受体(FGFR)改变导致的晚期癌症患者 融合和单核苷酸变异(SNV)，正受益于几种新的FGFR激酶抑制剂。 Erdafitinib和Pemigatinib最近被FDA批准用于膀胱癌和胆管癌， 和其他FGFR抑制剂已经获得了快速通道指定，并正在探索肿瘤 不可知论篮子试验。患者的总体存活率和无进展存活率都有所改善， 总体回复率高。不幸的是，几乎所有的患者最终都会对这些抑制剂产生抗药性， 通常是通过获得继发性FGFR突变。FGFR抑制剂的开发受到以下因素的阻碍 缺乏准确和全面的方法来1)快速检测FGFR的变化以确定患者的资格 对于临床试验，2)监测治疗反应，3)表征新出现的耐药性。这个 开发新的检测策略，如非侵入性液体活检，可以满足这些尚未满足的需求 诊断、预后和治疗选择。液体活组织检查评估血液样本，从中提取无细胞DNA 对肿瘤脱落的cfDNA进行测序，以检测基因组的变化。现有设备的技术规格 商业cfdna测试表明，这些检测没有得到fGFR融合的验证，并且存在不足。 对FGFR融合的敏感性约为30%。此外，商业测试规模太大，成本太高，无法重复 经常用于治疗和疾病监测。因此，我们建议开发并验证以FGFR为重点的、 用于实时检测的准确且经济高效的cfDNA测序分析(FGFR-Dx)，以支持快速检测， 反应监测，及早发现耐药性。我们在俄亥俄州立大学的团队有六个活跃的FGFR 抑制剂临床试验，一大批FGFR真阳性，以及临床实验室改进修正案 符合(CLIA)的癌症基因组学实验室，具有执行临床级肿瘤测序的丰富经验 以及用于检测和解释基因融合和单核苷酸变异的生物信息学分析。 此外，我们已经将cfdna的开发与快速研究尸检研究配对，这将使第一次 通过评估观察到的异质性的准确性来系统地评估cfDNA的检测限 来自多个部位的肿瘤样本在cfDNA中有表达。我们提出了以下目标来解决 PAR-18-317的标准：1)分析验证靶向液体活组织检查(FGFR-Dx)以检测融合 和FGFR1-3的单核苷酸变异(SNV)；2)建立FGFR-Dx检测FGFR的临床有效性 融合和SNV。总之，将以FGFR为重点的液体活检的开发与快速研究结合起来 尸检可以广泛影响该领域对cfDNA方法的理解和应用 FGFR改变的癌症和其他癌症。