Biomarker Developmental Unit

生物标志物开发单元

• 批准号: 10677831
• 负责人: CECILIA C YEUNG
• 金额: $ 26.42万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677831
• 关键词: Aberrant DNA Methylation; Address; Adherence; Aneuploidy; Barrett Epithelium; Barrett Esophagus; Biological Assay; Biological Markers; Biopsy; Cancer Etiology; Carcinoma; Cessation of life; Clinical; Clinical Trials; Collaborations; Colon; Colonic Adenoma; Colonoscopy; Colorectal Cancer; Custom; DNA; DNA Methylation; Development; Diagnostic Reagent Kits; Dysplasia; Early Detection Research Network; Early Diagnosis; Economic Burden; Ensure; Epigenetic Process; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophagus; Funding; Genetic Markers; Goals; High grade dysplasia; Individual; Laboratories; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of gastrointestinal tract; Massive Parallel Sequencing; Measures; Methods; Methylation; Mucous Membrane; Mutation; Pathology; Patients; Persons; Phase; Phase II/III Trial; Protocols documentation; Risk; Sampling; Screening for cancer; Serrated Adenoma; Testing; Tissue Sample; Tissues; Tubular Adenoma; Validation; biomarker panel; colon cancer risk; colon cancer screening; colorectal cancer risk; colorectal cancer screening; design; digital; early detection biomarkers; follow-up; high risk; high risk population; improved; industry partner; methylation biomarker; methylation testing; mortality; novel; patient stratification; phase IV trial; prevent; product development; programs; prospective; research clinical testing; risk prediction; risk stratification; risk variant; screening; screening program; social

PROJECT SUMMARY Background: Esophageal adenocarcinoma (EAC) arises from Barretts epithelium (BE) and colorectal cancer (CRC) arises from tubular and serrated adenomas, allowing for screening measures to prevent these cancers. The risk of CRC and EAC is variable and screening programs are most effective when optimized for high and low risk. However, our current methods for risk stratifying people are suboptimal, resulting in interval CRCs and EACs, which are preventable. In addition, current EAC screening tests are invasive and inconvenient, resulting in high social and economic burdens and low adherence. Epigenetic and genetic alterations are common in precursor lesions for CRC and EAC and can serve as early detection and as risk biomarkers for colon adenomas/CRC and BE/EAC, respectively. Hypothesis: For CRC, we hypothesis that a clinical testing program using methylated DNA biomarker assays in normal colonic mucosa will identify people at high risk of CRC who will benefit from more aggressive follow-up colonoscopies. For EAC, we hypothesize that clinical grade biomarkers assays based on epigenetic and genetic alterations for EAC risk prediction and early detection of high-grade dysplasia and early EAC in BE patients will improve EAC screening in BE patients and prevent EAC deaths. Proposal: We will clinically validate and develop GLP compliant assays, which can: 1) accurately detect high grade dysplasia (HGD) and early EAC; 2) can predict the risk of BE progression using DNA from either esophageal biopsies and ultimately brushings; and 3) can accurately identify people at high-risk for CRC, for whom aggressive CRC screening could be lifesaving. Assay design, protocols, controls, validation samples, and reference materials will be generated by the BDL and transferred to the BRL where the assays will undergo clinical validation. The BRL will develop harmonization and proficiency programs, along with GLP compliant kits in collaboration with industry partners to ensure other BCC BRLs can also conduct studies with these assays. BRL validated assays will support EDRN Phase 2/3 trials and will be based on a novel set of BDL discovered methylated DNA and genetic biomarkers that: 1) identify patients who are at increased risk of CRC from testing of normal colonic tissue biopsies; 2) improve risk stratification of patients with BE who are at increased risk of EAC and HGD using two classes of assays:one novel custom MPS assay and a smaller targeted MS-ddPCR assay, and 3) accurately detect HGD or early EAC in BE patients undergoing surveillance and that use esophageal brushing samples. Establishing proficiency testing programs with harmonized BRLs will ensure the biomarker tests are robust and reliable for Phase 2-4 clinical trials.

项目概要 背景：食管腺癌 (EAC) 起源于 Barretts 上皮 (BE) 和结直肠癌 （CRC）由管状和锯齿状腺瘤产生，允许采取筛查措施来预防这些癌症。 CRC 和 EAC 的风险是可变的，筛查计划在针对高风险和高风险进行优化时最为有效。 低风险。然而，我们目前对人群进行风险分层的方法并不理想，导致区间 CRC 和 EAC，这是可以预防的。此外，目前的 EAC 筛查测试具有侵入性且不方便，导致 社会和经济负担高，依从性低。表观遗传和遗传改变常见于 CRC 和 EAC 的前兆病变，可作为结肠的早期检测和风险生物标志物 分别为腺瘤/CRC 和 BE/EAC。假设：对于 CRC，我们假设临床测试计划 在正常结肠粘膜中使用甲基化 DNA 生物标志物检测将识别出患有 CRC 高危人群 将从更积极的后续结肠镜检查中受益。对于 EAC，我们假设临床等级 基于表观遗传和遗传改变的生物标志物测定，用于 EAC 风险预测和早期检测 BE 患者的高度不典型增生和早期 EAC 将改善 BE 患者的 EAC 筛查并预防 EAC 死亡人数。 建议：我们将进行临床验证并开发符合 GLP 的检测方法，该检测方法可以：1）准确检测高浓度 级别不典型增生 (HGD) 和早期 EAC； 2) 可以使用任一来源的 DNA 预测 BE 进展的风险 食管活检并最终进行刷检； 3）能够准确识别CRC高危人群， 积极的结直肠癌筛查可以挽救生命。测定设计、方案、对照、验证样品、 参考材料将由 BDL 生成并转移到 BRL，在那里进行分析 临床验证。 BRL 将开发协调和熟练程度计划以及符合 GLP 的套件 与行业合作伙伴合作，确保其他 BCC BRL 也可以使用这些检测进行研究。 BRL 验证的检测将支持 EDRN 2/3 期试验，并将基于发现的一组新颖的 BDL 甲基化 DNA 和遗传生物标志物：1) 通过检测识别 CRC 风险增加的患者 正常结肠组织活检； 2）改善BE患者的风险分层，这些患者的风险增加 EAC 和 HGD 使用两类检测：一种新颖的定制 MPS 检测和一种较小的靶向 MS-ddPCR 分析，3) 在接受监测的 BE 患者中准确检测 HGD 或早期 EAC，并使用 食管刷检样本。建立具有统一 BRL 的能力验证计划将确保 生物标志物测试对于 2-4 期临床试验来说是稳健且可靠的。