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: 10456192
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456192
• 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; Prognosis; Protocols documentation; Resected; Sampling; Specimen; Surveillance Program; Survival Rate; Techniques; Technology; Testing; Time; Tissues; Training; Treatment Cost; United States; Upper digestive tract structure; accurate diagnostics; analytical method; base; biomarker panel; bisulfite; capsule; clinical translation; cohort; cost; diagnostic accuracy; diagnostic assay; diagnostic strategy; epigenetic marker; experience; improved; industry partner; methylation biomarker; minimally invasive; nano; 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.

巴雷特食管（BE）是食管癌危险的专性癌前病变。 腺癌（EAC）是美国增长最快且致命的恶性肿瘤之一 欧洲(3)。EAC 在变得具有侵入性且无法治疗之前很少被发现，并且 95% 的 EAC 发生于 相比之下，之前未诊断出 BE 的患者(19)(20) 则诊断为 BE 的患者表现良好。 预后，因为肿瘤很早就可以通过定期内窥镜监测发现。 目前可进行基于微创、低成本生物标志物的临床转化筛查试验。 通过结合我们的技术，BE 诊断方法将改善早期 EAC 检测并提高总体生存率。 由我们的工业制造的可吞咽、可回收的食管样本采集海绵 (EsophaCapTM) 合作伙伴 Capnostics 拥有我们的专利 BE DNA 甲基化标记和增强的处理能力 珠子甲基化 (MOB) 技术可最大限度地提高 DNA 的提取和亚硫酸氢盐转化率； 在我们的工业合作伙伴 MyGenetx 的符合 CLIA 标准的实验室中建立此测定法，我们现在可以进行 这种广泛可用的初步数据表明我们基于海绵的诊断准确性很高。 BE 的生物标志物测试 我们将通过追求以下具体目标来应用该策略： 目标 1. 分析。 首先，使用技术复制 EsophaCapTM 验证我们基于 EsophaCapTM 的 BE 诊断测定。 来自 42 名新招募的 BE 患者和 42 名非 BE 对照的标本，我们将确认准确性， 我们的 BE 诊断测定的稳健性和可靠性也令人鼓舞。 （参见表 2，技术重复）接下来，在这些相同的 42 名已知 BE 患者中与 42 名对照者中进行比较。 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 目标 2. 进行试点研究以验证基于 EsophaCapTM 的多变量模型。 基于我们已经收集的 EsophaCapTM 衍生样本训练数据集（见图 5）， 我们已经构建了 BE 的 3 标记预测模型（图 6）。我们将应用该模型和所选的切分。 关闭阈值到新收集的 50 个未经测试的样本（独立于目标 1 样本）。 在 BE 测试组中前瞻性测试组合的海绵甲基化生物标志物策略 我们的检测将在来自前瞻性研究的 EsophaCapTM 衍生样本中进行。 目标 2 中验证的多变量模型将应用于收集的 80 名 BE 患者和 240 名对照队列。 目标 4. 并行实现我们的 EsophaCapTM 检测方案的工业化。 与目标 1-3 同时，我们将建立基于 MOB 的 DNA 提取、亚硫酸氢盐的所有步骤 在符合 CLIA 标准的实验室中进行修饰和定量甲基化特异性 PCR (qMSP) 方案 将通过从同一患者获取重复海绵来重复目标 3 中进行的测定， 这次是在 CLIA 实验室，并通过与 Aim 3 结果进行比较来检查准确性。

项目成果

Striking heterogeneity of somatic L1 retrotransposition in single normal and cancerous gastrointestinal cells.

单个正常和癌性胃肠道细胞中体细胞 L1 逆转录转座的惊人异质性。

• DOI: 10.1073/pnas.2019450117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yamaguchi,Katsumi;Soares,AlishaO;Goff,LoyalA;Talasila,Anjali;Choi,JungbinA;Ivenitsky,Daria;Karma,Sadik;Brophy,Benjamin;Devine,ScottE;Meltzer,StephenJ;KazazianJr,HaigH
• 通讯作者: KazazianJr,HaigH

Novel Long Noncoding RNA miR205HG Functions as an Esophageal Tumor-Suppressive Hedgehog Inhibitor.

• DOI: 10.3390/cancers13071707
• 发表时间: 2021-04-03
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Song JH;Tieu AH;Cheng Y;Ma K;Akshintala VS;Simsek C;Prasath V;Shin EJ;Ngamruengphong S;Khashab MA;Abraham JM;Meltzer SJ
• 通讯作者: Meltzer SJ

Modeling Wnt signaling by CRISPR-Cas9 genome editing recapitulates neoplasia in human Barrett epithelial organoids.

• DOI: 10.1016/j.canlet.2018.08.017
• 发表时间: 2018-11-01
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Liu X;Cheng Y;Abraham JM;Wang Z;Wang Z;Ke X;Yan R;Shin EJ;Ngamruengphong S;Khashab MA;Zhang G;McNamara G;Ewald AJ;Lin D;Liu Z;Meltzer SJ
• 通讯作者: Meltzer SJ

Synthetic Circular RNA Functions as a miR-21 Sponge to Suppress Gastric Carcinoma Cell Proliferation.

• DOI: 10.1016/j.omtn.2018.09.010
• 发表时间: 2018-12-07
• 期刊: Molecular therapy. Nucleic acids
• 作者: Liu X;Abraham JM;Cheng Y;Wang Z;Wang Z;Zhang G;Ashktorab H;Smoot DT;Cole RN;Boronina TN;DeVine LR;Talbot CC Jr;Liu Z;Meltzer SJ
• 通讯作者: Meltzer SJ

Accurate Nonendoscopic Detection of Esophageal Squamous Cell Carcinoma Using Methylated DNA Biomarkers.

• DOI: 10.1053/j.gastro.2022.04.021
• 发表时间: 2022-08
• 期刊: Gastroenterology
• 影响因子: 29.4