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

基本信息

  • 批准号:
    10282372
  • 负责人:
  • 金额:
    $ 24.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
液体活检用于快速检测和实时监测 FGFR 改变的癌症 因成纤维细胞生长因子受体 (FGFR) 改变(包括基因改变)导致的晚期癌症患者 融合和单核苷酸变异 (SNV) 正受益于几种新型 FGFR 激酶抑制剂。 Erdafitinib 和 pemigatinib 最近被 FDA 批准用于治疗膀胱癌和胆管癌, 分别,其他 FGFR 抑制剂已获得快速通道指定,并正在肿瘤中进行探索 不可知的篮子试验使患者的总生存期和无进展生存期得到改善。 不幸的是,几乎所有患者最终都会对这些抑制剂产生耐药性, 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 改变以确定患者资格 对于临床试验,2) 监测治疗反应,3) 描述新出现的耐药性。 开发新的检测策略,例如非侵入性液体活检,可以满足这些未满足的需求 液体活检评估血液样本,从中提取游离 DNA。 对肿瘤脱落的(cfDNA)进行测序以检测现有的基因组改变。 商业 cfDNA 测试表明,这些测定方法未针对 FGFR 融合进行验证,并且没有足够的证据 FGFR 融合的敏感性约为 30% 此外,商业测试规模太大且重复成本高昂。 因此,我们建议开发和验证以 FGFR 为重点的、 准确且经济高效的 cfDNA 测序测定 (FGFR-Dx),用于实时测试以支持快速检测, 反应监测和耐药性的早期检测 我们俄亥俄州立大学的团队有 6 个活跃的 FGFR。 抑制剂临床试验、一大群 FGFR 真阳性以及临床实验室改进修正案 符合 (CLIA) 标准的癌症基因组学实验室,拥有丰富的临床级肿瘤测序经验 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,我们将这种 cfDNA 开发与快速尸检研究相结合,这将使第一个 通过评估观察到的异质性的准确程度,系统评估 cfDNA 的检测限 我们提出以下目标来解决来自多个位点的肿瘤样本的问题。 PAR-18-317 的标准:1) 分析验证靶向液体活检测定 (FGFR-Dx) 以检测融合 2) 确定 FGFR-Dx 检测 FGFR 的临床有效性; 总之,将 FGFR 液体活检的发展与快速研究结合起来。 尸检可以广泛影响该领域对 cfDNA 方法在患者中的理解和应用 FGFR 改变和其他癌症。

项目成果

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Sameek Roychowdhury其他文献

Sameek Roychowdhury的其他文献

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{{ truncateString('Sameek Roychowdhury', 18)}}的其他基金

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:
    10922903
  • 财政年份:
    2021
  • 资助金额:
    $ 24.24万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 24.24万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 24.24万
  • 项目类别:
Assay Validation of Targeted RNA sequencing to Detect Kinase Gene Fusions
用于检测激酶基因融合的靶向 RNA 测序的分析验证
  • 批准号:
    10005278
  • 财政年份:
    2016
  • 资助金额:
    $ 24.24万
  • 项目类别:
Assay Validation of Targeted RNA sequencing to Detect Kinase Gene Fusions
用于检测激酶基因融合的靶向 RNA 测序的分析验证
  • 批准号:
    9041381
  • 财政年份:
    2016
  • 资助金额:
    $ 24.24万
  • 项目类别:
Assay Validation of Targeted RNA sequencing to Detect Kinase Gene Fusions
用于检测激酶基因融合的靶向 RNA 测序的分析验证
  • 批准号:
    9762047
  • 财政年份:
    2016
  • 资助金额:
    $ 24.24万
  • 项目类别:

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