Academic-Industrial Partnership for Non-invasive Barrett's Esophagus Detection

无创巴雷特食管检测的学术与工业合作伙伴关系

• 批准号: 10015265
• 负责人: Stephen J Meltzer
• 金额: $ 74.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015265
• 关键词: Barrett Esophagus; Benign; Biological Assay; Biological Markers; Biopsy Specimen; CLIA certified; Carcinoma in Situ; Clinic; Clinical; Collecting Cell; Collection; Coupled; DNA; DNA Methylation; Dangerousness; Data; Data Set; Deglutition; Detection; Development; Devices; Diagnosis; Diagnostic; Dysplasia; Early Diagnosis; Endoscopy; Enrollment; Epigenetic Process; Esophageal Adenocarcinoma; Esophagus; Europe; Fatality rate; Gelatin; Genetic; Goals; High grade dysplasia; Industrialization; Laboratories; Legal patent; Lesion; Life; Malignant Neoplasms; Methods; Methylation; Modality; Modeling; Modification; Nanotechnology; Neoplasms; Patients; Periodicity; Pilot Projects; Porifera; Protocols documentation; Resected; Sampling; Specimen; Surveillance Program; Survival Rate; Techniques; Technology; Testing; Time; Tissues; Training; Treatment Cost; United States; Upper digestive tract structure; analytical method; base; biomarker panel; bisulfite; capsule; clinical translation; cohort; cost; diagnostic accuracy; diagnostic assay; epigenetic marker; experience; improved; industry partner; methylation biomarker; minimally invasive; nano; outcome forecast; patient population; predictive modeling; premalignant; prospective; prospective test; recruit; sample collection; screening; tumor

Barrett’s esophagus (BE) is the dangerous obligate premalignant precursor lesion of esophageal adenocarcinoma (EAC), one of the most rapidly increasing and lethal malignancies in the United States and Europe(3). EAC is rarely detected before it becomes invasive and untreatable, and 95% of EACs develop in patients not previously diagnosed with BE(19)(20). Patients diagnosed with BE, in contrast, have an excellent prognosis, since neoplasia is detected very early by periodic endoscopic surveillance. There is, however, no currently available screening test for BE. Clinical translation of minimally invasive, low-cost biomarker-based approaches to BE diagnosis will improve early EAC detection and increase overall survival. By combining our swallowable, retrievable esophageal sample collection sponge (EsophaCapTM) manufactured by our industrial partner, Capnostics, with our patented BE DNA methylation markers and our enhanced processing technique, Methylation-On-Beads (MOB) to maximize extraction and bisulfite conversion of DNA; and by establishing this assay in the CLIA-compliant laboratory of our industrial partner, MyGenetx, we can now make this assay widely available. Preliminary data demonstrate high diagnostic accuracy of our sponge-based biomarker test for BE. We will apply this strategy by pursuing the following Specific Aims: Aim 1. To analytically validate our EsophaCapTM-based BE diagnostic assay. Aim 1a. First, using technical replicate EsophaCapTM specimens from 42 newly recruited BE patients and 42 non-BE controls, we will confirm the accuracy, robustness, and reliability of our BE diagnostic assay. Preliminary results in this context are also encouraging (see Table 2, Technical replicates). Aim 1b. Next, in these same 42 patients with known BE vs. 42 controls without BE, we will establish analytical concordance of EsophaCapTM-based data with matched tissue biopsy sample data. Aim 2. To conduct a pilot study to validate a multivariate model for EsophaCapTM-based diagnosis of BE. Based on our already-collected EsophaCapTM-derived specimen training dataset (see Fig. 5), we have constructed a 3-marker prediction model for BE (Fig. 6). We will apply this model and the chosen cut- off threshold to a newly collected set of 50 untested samples (independent of the Aim 1 samples). Aim 3. To prospectively test the combined sponge-methylation biomarker strategy in a test set cohort of BE patients vs. controls. Our assay will be performed in EsophaCapTM-derived samples from a prospectively- collected cohort of 80 BE patients and 240 controls. The multivariate model validated in Aim 2 will be applied to this test set of large patient population. Aim 4. To industrialize our EsophaCapTM assay protocol. In parallel and simultaneously with Aims 1-3, we will establish all steps in our MOB-based DNA extraction, bisulfite modification and quantitative methylation-specific PCR (qMSP) protocol in the CLIA-compliant laboratory at MyGenetx. Assays performed in Aim 3 will be repeated by obtaining repeat sponges from the same patients, this time in the CLIA lab, and checked for accuracy by comparison to Aim 3 results.

Barrett‘s食道(BE)是一种危险的食管癌前病变 腺癌(EAC)是美国增长最快、最致命的恶性肿瘤之一， 欧洲(3)。EAC在变得侵袭性和不可治疗之前很少被检测到，95%的EAC发生在 以前未被诊断为BE的患者(19)(20)。相比之下，被诊断为BE的患者具有极好的 预后，因为通过定期的内窥镜监测很早就发现了肿瘤。然而，没有 目前可用于BE的筛查试验。基于微创、低成本生物标志物的临床翻译 确诊的方法将改善EAC的早期检测，提高总体存活率。通过将我们的 我们工业生产的可吞咽、可回收的食道样本采集海绵(EsophaCapTM) Capnostics合作伙伴，拥有我们的专利BE DNA甲基化标记和我们增强的处理 技术，珠上甲基化(MOB)，以最大限度地提高DNA的提取和亚硫酸氢盐转化；以及通过 在我们的工业合作伙伴MyGenetx的符合CLIA的实验室中建立这种测试，我们现在可以制造 这种检测方法随处可见。初步数据表明，我们基于海绵的诊断准确率很高 BE的生物标志物检测。我们将通过追求以下具体目标来应用这一战略：目标1.分析 验证我们基于EsophaCapTM的BE诊断分析。目标1a。首先，使用技术复制EsophaCapTM 新招募的42例BE患者和42例非BE对照的标本，我们将确认其准确性， 我们BE诊断试验的稳健性和可靠性。这方面的初步结果也令人鼓舞。 (见表2，技术复制)。目标1b。接下来，在这42名已知BE患者和42名对照患者中 如果没有BE，我们将建立基于EsophaCapTM的数据与匹配的组织活检的分析一致性 样本数据。目的2.进行一项初步研究，以验证基于EsophaCapTM的多变量模型 BE的诊断。基于我们已经收集的EsophaCapTM导出的样本训练数据集(参见图5)， 我们已经构建了BE的3标记预测模型(图6)。我们将应用此模型和选定的切割- 新收集的一组50个未测试样本(与目标1样本无关)的阈值。目标3.至 前瞻性地在BE的测试集队列中测试海绵-甲基化联合生物标记物策略 患者与对照组。我们的分析将在EsophaCapTM衍生的样本中进行，这些样本来自预期的- 收集了80例BE患者和240例对照的队列。在AIM 2中验证的多变量模型将应用于 这个测试集的患者群体很大。目的4.对我们的EsophaCapTM检测方法进行工业化。并行的 同时，与AIMS 1-3一起，我们将建立基于MOB的DNA提取的所有步骤，亚硫酸氢盐 符合CLIA标准的实验室中的修改和定量甲基化特异性聚合酶链式反应(QMSP)协议，网址为 MyGenetx。在AIM 3中执行的分析将通过从相同患者获得重复的海绵来重复， 这一次是在CLIA实验室，并通过与AIM 3的结果进行比较来检查准确性。