Innovative approach to cancer detection and treatment monitoring

癌症检测和治疗监测的创新方法

基本信息

  • 批准号:
    8426388
  • 负责人:
  • 金额:
    $ 22.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-01 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): It is now well established that cell-free tumor DNA is released into the blood of cancer patients. In theory, this presents a potentially powerful opportunity to develop biomarkers for a variety of clinical applications including cancer detection, monitoring of response to therapy and detection of recurrent disease. To date however, this potential remains mostly unrealized. This is due to several factors. First, circulating, cell-free DNA is found at low concentrations (ng/ml) in plasma/serum and is mostly present as small fragments. This has historically made isolation of adequate DNA quantities for testing difficult. In addition, the majority of circulating, cell-free DNA is from normal cells not tumor cells, thus presenting a "needle in a haystack" problem. Finally, widely available and robust analytical tools capable of detecting rare, tumor-associated DNA alterations have for the most part been lacking. Furthermore, those tools that are available require a priori knowledge of the specific tumor-associated mutations to be detected in the plasma and therefore are not suitable for de novo cancer detection tests. In this application, we will use novel data and innovative technologies in order to overcome these issues and to determine the potential of circulating, cell-free tumor DNA as a biomarker for detection and treatment monitoring in patients with esophageal adenocarcinoma (EAC). Specifically, we will use a multiplex PCR- based pre-amplification technology (AmpliSeq(tm)) to generate next-generation sequencing libraries targeting >66Kb of DNA from the coding regions of 20 genes found to be frequently mutated in EAC. This technology is specifically designed to be compatible with nanogram inputs of highly fragmented DNA and we have successfully used it to sequence the 20 genes in tumor samples and in cell-free DNA from plasma. Average per-base read depth using Ion Torrent semi-conductor sequencing in these samples is >2000x and can easily be increased further. Thus we believe that we can detect mutations at any base in the target genes with detection sensitivity of 0.5% tumor DNA fraction or less. Complementing this novel sequencing approach, we will use another new technology, droplet digital PCR (ddPCR), to quantify tumor associated mutations in plasma with even lower sensitivity (<0.001%). In Specific Aim 1, these technologies combined will allow us to determine the feasibility of a next-generation, deep sequencing-based approach to cancer detection. Next, we will use these same technologies to address another important clinical issue in the management of patients with EAC: dynamic monitoring of response to neoadjuvant therapy. Up to 40% of patients do not respond to neoadjuvant therapy and are thus exposed to the associated toxicity and cost without benefit. Furthermore, potentially curative surgical therapy is delayed in these patients, some of whom progress to the point where surgery is no longer an option. In Specific Aim 2, we will use ddPCR to determine whether circulating tumor DNA load can be used to rapidly and dynamically identify response or resistance to neoadjuvant therapy.
描述(申请人提供):现已证实无细胞肿瘤DNA被释放到癌症患者的血液中。从理论上讲,这为开发各种临床应用的生物标记物提供了一个潜在的强大机会,包括癌症检测、治疗反应监测和复发疾病的检测。然而,到目前为止,这种潜力大多仍未实现。这是由几个因素造成的。首先,循环中的无细胞DNA在血浆/血清中的浓度很低(ng/ml),并且大多以小片段的形式存在。从历史上看,这使得分离出足够数量的DNA用于测试变得困难。此外,大多数循环中的无细胞DNA来自正常细胞,而不是 肿瘤细胞,因此出现了“大海捞针”的问题。最后,能够检测罕见的与肿瘤相关的DNA变化的广泛可用和强大的分析工具在很大程度上是缺乏的。此外,这些可用的工具需要在血浆中检测特定肿瘤相关突变的先验知识,因此不适用于从头开始的癌症检测测试。在这项应用中,我们将使用新的数据和创新的技术来克服这些问题,并确定循环中的无细胞肿瘤DNA作为检测和治疗监测食管腺癌(EAC)患者的生物标志物的潜力。具体地说,我们将使用基于多重PCR的预扩增技术(AmpliSeq(Tm))来生成下一代测序库,目标是从EAC中发现频繁突变的20个基因的编码区中获得66Kb的DNA。这项技术是专门为兼容纳克输入的高度碎片DNA而设计的,我们已经成功地使用它对肿瘤样本中的20个基因和来自血浆的无细胞DNA进行了测序。在这些样品中,使用Ion Torrent半导体测序的每个碱基的平均读取深度是&gt;2000x,并且可以很容易地进一步增加。因此,我们相信,我们可以检测到靶基因中任何碱基的突变,检测灵敏度为0.5%或更低的肿瘤DNA片段。作为对这一新测序方法的补充,我们将使用另一种新技术,液滴数字聚合酶链式反应(DdPCR),以更低的灵敏度(&lt;0.001%)定量检测血浆中的肿瘤相关突变。在具体目标1中,这些技术的结合将使我们能够确定下一代、基于深度测序的癌症检测方法的可行性。接下来,我们将使用这些相同的技术来解决EAC患者管理中的另一个重要临床问题:动态监测对新辅助治疗的反应。高达40%的患者对新辅助治疗没有反应,因此暴露在相关的毒性和成本之下,而没有受益。此外,在这些患者中,潜在的根治手术治疗被推迟,其中一些患者进展到不再选择手术的地步。在特定的目标2中,我们将使用ddPCR来确定循环肿瘤DNA负载是否可以用于快速和动态地识别对新辅助治疗的反应或抵抗。

项目成果

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会议论文数量(0)
专利数量(1)

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Tony E Godfrey其他文献

Tony E Godfrey的其他文献

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{{ truncateString('Tony E Godfrey', 18)}}的其他基金

Development of diagnostic and prognostic tests for esophageal adenocarcinoma
食管腺癌诊断和预后测试的发展
  • 批准号:
    10057357
  • 财政年份:
    2016
  • 资助金额:
    $ 22.67万
  • 项目类别:
Development of diagnostic and prognostic tests for esophageal adenocarcinoma
食管腺癌诊断和预后测试的发展
  • 批准号:
    10308014
  • 财政年份:
    2016
  • 资助金额:
    $ 22.67万
  • 项目类别:
Feasibility of Molecular Cytology for the Management of Barrett's Esophagus
分子细胞学治疗巴雷特食管的可行性
  • 批准号:
    8880446
  • 财政年份:
    2015
  • 资助金额:
    $ 22.67万
  • 项目类别:
Innovative approach to cancer detection and treatment monitoring
癌症检测和治疗监测的创新方法
  • 批准号:
    8643777
  • 财政年份:
    2013
  • 资助金额:
    $ 22.67万
  • 项目类别:
Immunobiology of Trauma
创伤免疫生物学
  • 批准号:
    10159264
  • 财政年份:
    2010
  • 资助金额:
    $ 22.67万
  • 项目类别:
Impact of Biological, Clinical, and Social Determinants on Trauma and Trauma Outcomes
生物学、临床和社会决定因素对创伤和创伤结果的影响
  • 批准号:
    10344300
  • 财政年份:
    2010
  • 资助金额:
    $ 22.67万
  • 项目类别:
Impact of Biological, Clinical, and Social Determinants on Trauma and Trauma Outcomes
生物学、临床和社会决定因素对创伤和创伤结果的影响
  • 批准号:
    10616684
  • 财政年份:
    2010
  • 资助金额:
    $ 22.67万
  • 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
  • 批准号:
    7909276
  • 财政年份:
    2009
  • 资助金额:
    $ 22.67万
  • 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
  • 批准号:
    7687433
  • 财政年份:
    2008
  • 资助金额:
    $ 22.67万
  • 项目类别:
Biomarkers for Esophageal Cancer Progression and Prognosis
食管癌进展和预后的生物标志物
  • 批准号:
    7523588
  • 财政年份:
    2008
  • 资助金额:
    $ 22.67万
  • 项目类别:

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量子化学挑战阐明碱基序列特异性决定去除 DNA 损伤的功能机制
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