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.

巴雷特的食管（BE）是食管食管的危险强制性前体病变 腺癌（EAC），美国和致命性最快，致命性恶性肿瘤之一 欧洲（3）。 EAC在侵入性和无法治疗之前很少被检测到，而95％的EAC在 以前未被诊断为BE（19）（20）的患者。相比之下，被诊断出BE的患者具有出色的 预后，由于周期性内窥镜监测很早就发现了肿瘤。但是，没有 当前可用的BE筛选测试。微创，低成本生物标志物的临床翻译 成为诊断方法的方法将改善EAC的早期检测并增加总体生存。通过结合我们 我们工业制造 合作伙伴，Capnostics，我们获得的DNA甲基化标记和我们的加工 技术，甲基化甲基化（MOB），以最大程度地提取DNA的提取和甲基硫酸甲基转化率；和 在我们的工业合作伙伴MyGenetx的Clia兼容实验室中建立该测定法 该测定广泛可用。初步数据证明了我们的赞助商的诊断准确性高 BE生物标志物测试。我们将通过追求以下特定目标来应用此策略：目标1。 验证我们的基于食管的诊断测定法。目标1a。首先，使用技术复制食管 来自42名新招募的患者和42个非对照的标本，我们将确认准确性， 鲁棒性和我们的诊断测定的可靠性。在这种情况下的初步结果也令人鼓舞 （请参阅表2，技术重复）。目标1B。接下来，在这42例已知患者中，是42例对照 没有BE，我们将与匹配的组织活检建立基于食道的数据的分析一致性 示例数据。目标2。进行试验研究以验证基于食管的多元模型 诊断BE。基于我们已经收集的食管衍生的标本训练数据集（见图5）， 我们已经为BE构建了一个3标记的预测模型（图6）。我们将应用此模型和选定的切割 - 脱离阈值到新收集的50个未经测试的样本（与AIM 1样本无关）。目标3 前瞻性测试在测试集的BE中的合并赞助商 - 甲基化生物标志物策略 患者与对照组。我们的评估将在前瞻性的食管衍生样品中进行 收集的80例患者和240个对照组收集的队列。 AIM 2中验证的多元模型将应用于 这套大量患者人群的测试集。目的4。工业化我们的食道测定方案。并联 仅用目标1-3，我们将在基于暴民的DNA提取，甲硫酸盐中建立所有步骤 Clia符合实验室的修改和定量甲基化特异性PCR（QMSP）方案 mygenetx。在AIM 3中进行的测定将通过获得同一患者的重复海绵来重复 这次在Clia实验室中，并通过与AIM 3结果相比，检查了准确性。

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