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.

项目摘要 背景：食管腺癌起源于Barretts上皮和结直肠癌 (CRC)源于管状和锯齿状腺瘤，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，当针对高风险和低风险进行优化时，筛查程序是最有效的。 低风险。然而，我们目前的风险分层方法是次优的，导致间隔CRC和 EACs是可以预防的。此外，目前的EAC筛查测试是侵入性的和不方便的，导致 社会和经济负担高，坚持率低。表观遗传学和遗传学改变在 CRC和EAC的前体病变，可作为结肠癌的早期检测和风险生物标志物 腺瘤/CRC和BE/EAC。假设：对于CRC，我们假设临床测试程序 在正常结肠粘膜中使用甲基化DNA生物标志物测定将识别CRC高危人群， 会从更积极的结肠镜检查中受益对于EAC，我们假设临床级别 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患者中高度异型增生和早期EAC将改善BE患者中EAC的筛查并预防EAC 死亡 提案：我们将临床验证和开发符合GLP的检测方法，该方法可以：1）准确检测高浓度的 分级异型增生（HGD）和早期EAC; 2）可以使用来自以下任一种的DNA预测BE进展的风险： 食管活检和最终刷;和3）可以准确地识别CRC高危人群， 积极的CRC筛查可以挽救生命。试验设计、方案、对照品、验证样品， BDL将生成参考材料，并将其转移至BRL，在BRL中进行测定 临床验证BRL将制定协调和熟练程度计划，沿着GLP合规套件 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，并将基于一组新的BDL发现 甲基化DNA和遗传生物标志物：1）从检测中识别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， EAC和HGD使用两类检测试剂：一种新型定制MPS检测试剂和一种较小的靶向MS-ddPCR 检测，和3）准确地检测HGD或早期EAC在BE患者进行监测和使用 食道刷检样本。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期临床试验是稳健和可靠的。