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（EAC）来自Barretts上皮（BE）和大肠癌 （CRC）由管状和锯齿状的腺瘤产生，可以采取筛查措施以防止这些癌症。 CRC和EAC的风险是可变的，在对高和高的优化时，筛选程序最有效 低风险。但是，我们当前的风险分层方法是次优的，导致间隔CRC和 可预防的EAC。此外，当前的EAC筛查测试是侵入性和不便的，因此 在高昂的社会和经济负担和依从性低下。表观遗传和遗传改变在 CRC和EAC的前体病变，可以作为早期检测，并作为结肠的风险生物标志物 腺瘤/CRC和BE/EAC。假设：对于CRC，我们假设临床测试计划 在正常结肠粘膜中使用甲基化的DNA生物标志物测定将确定CRC高风险的人 将受益于更具侵略性的随访结肠镜检查。对于EAC，我们假设临床等级 基于EAC风险预测的表观遗传和遗传改变的生物标志物测定和早期检测 患者的高级发育不良和早期EAC将改善患者的EAC筛查，并防止EAC 死亡人数。 提案：我们将在临床上验证和开发符合GLP的测定，该测定可以：1）准确检测到高度 等级发育不良（HGD）和早期EAC； 2）可以预测使用来自任何一个的DNA的BE进展的风险 食管活检，最终刷牙； 3）可以准确地确定CRC高风险的人，因为 激进的CRC筛查可以挽救生命。测定设计，协议，控件，验证样本， 和参考材料将由BDL生成，并转移到BRL，在该BRL中将进行测定 临床验证。 BRL将开发协调和熟练计划，以及符合GLP的套件 与行业合作伙伴合作，以确保其他BCC BRL也可以通过这些测定法进行研究。 BRL验证的测定法将支持EDRN阶段2/3试验，并将基于发现的新型BDL 甲基化的DNA和遗传生物标志物：1）鉴定患者患有CRC风险增加的患者 正常的结肠组织活检； 2）改善患有增加风险的患者的风险分层 EAC和HGD使用两类测定法：一种新颖的自定义MPS分析和一个较小的目标MS-DDPCR 分析和3）在接受监视的患者中准确检测到HGD或EAC早期EAC 食管刷样品。建立具有统一BRL的能力测试计划将确保 生物标志物测试对于2-4阶段的临床试验非常可靠。