CMA- Marker-assisted prevention and risk stratification (MAPRS): Mucin signatures and molecular imaging for the early detection of colorectal cancer.

CMA-标记辅助预防和风险分层（MAPRS）：用于早期检测结直肠癌的粘蛋白特征和分子成像。

• 批准号: 9665195
• 负责人: Michael Bouvet
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9665195
• 关键词: Address; Adherence; Adjuvant; Affect; Age; Algorithms; Antibodies; Artificial Intelligence; Biological Assay; Biological Markers; Blood; Blood Tests; Cancer Etiology; Cessation of life; Classification; Clinical; Colon; Colon Carcinoma; Colonic Polyps; Colonoscopy; Colorectal Cancer; Data; Detection; Development; Diagnosis; Diagnostic; Distant; Dysplasia; Early Diagnosis; Endoscopy; Ensure; Excision; Fecal occult blood; Fluorescence; Future; Genomics; Histologic; Image; Imaging technology; Incidence; Intervention; Label; Lesion; Link; Localized Disease; Malignant - descriptor; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Molecular; Mucin-2 Staining Method; Mucins; Mus; Nature; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Polypectomy; Polyps; Polysaccharides; Population; Pre-Clinical Model; Precision therapeutics; Prevention; Recommendation; Rectal Neoplasms; Recurrence; Risk; Risk Reduction; Risk stratification; Sampling; Sensitivity and Specificity; Serrated Adenoma; Serum; Side; Surface; Surgical Oncology; Surgical margins; Testing; Tissues; Transgenic Mice; Veterans; Visualization; Xenograft procedure; adenoma; antibody conjugate; base; biobank; biomarker panel; cancer cell; cancer diagnosis; clinical application; colon cancer patients; colon cancer screening; colorectal cancer metastasis; colorectal cancer prevention; colorectal cancer progression; colorectal cancer risk; colorectal cancer screening; combinatorial; cost; differential expression; evidence base; fluorescence-guided surgery; fluorophore; glycosylation; high risk; image guided; improved; in silico; mathematical model; metastatic colorectal; molecular imaging; mortality; mouse model; novel; personalized management; predictive modeling; premalignant; pressure; response; screening; success; synergism; treatment strategy; tumor

PROJECT SUMMARY ABSTRACT CMA: Marker-assisted prevention and risk stratification (MAPRS): Mucin signatures and their molecular imaging for the early detection of colorectal cancer Herein, a group of collaborative merit review applications (CMA) aim to advance precision management of cancers, especially focusing on marker-assisted prevention and risk stratification (MAPRS) of colorectal cancers (CRCs), which is the third major cancer in the USA and accounts for 9.5% of all cancers among Veterans. While screening colonoscopy has emerged as perhaps the most effective lifesaving intervention against CRC to date, their successes have been limited by ease-of-use and downward cost pressures. Also, despite high R0 resection rates in patients with CRC, local and distant recurrence is still a significant problem and has been cited as high as 40 per cent. The proposed CMAs aim to address these limitations and to significantly disrupt CRC prevention, detection, risk stratification and precision treatment by advancing MAPRS. The projects include the followings. CMA1 aims to develop artificial intelligence enhanced endoscopy for colorectal cancer prevention. CMA2 plans to examine mucin-based markers for improved endoscopic detection, resection, histological classification and surveillance of pre-malignant colonic polyp (sessile serrated adenoma/polyps and adenoma) and examine their clinical utility as an adjunct to screening colonoscopy. CMA3 proposes to validate tissue and blood-based combinatorial biomarker panels, derived from functional pathway-specific studies, to improve the early detection of colon cancer and stratify populations according to their risk for developing CRC. Finally, CMA4 plans to examine the genomic and/or cellomic drug response profiling using patients’ tumor discards and develop a tumor-on-chip platform toward an evidence- based precision treatment strategy for CRCs. These CMRs are linked both intrinsically among each other and extrinsically with VA colorectal cancer cellgenomics consortium (VA4C) to maximize synergy and ensure success. Rationale: With a lifetime development risk of 5%, CRC is the third-most common cancer and the second major cause of cancer-related deaths. Colonoscopy polypectomy during screening have significantly reduced both incidence and overall mortality. Further, even after widespread use of screening colonoscopy, there is an age-adjusted incidence of and mortality from prevalent, right-sided CRCs. Major proportion of these tumors emerge from sessile serrated adenoma/polyps (SSA/Ps) that have gone undetected during initial colonoscopy. Furthermore, only 40% of CRCs are diagnosed at early stage, in part due to lack of compliance and to low sensitivity and specificity of the more common tests, including fecal occult blood tests and the insidious (asymptomatic) nature of localized disease. Our preliminary data suggest altered expression of various mucins during CRC progression, characterized by aberrant localization and glycosylation and differential expression. Based on preliminary studies and the identified gaps in diagnosis, we hypothesize that a serum based combinatorial biomarker panel based on altered expression and glycosylation of mucins will serve as a powerful adjunct to colonoscopy and will improve surveillance efficiency, endoscopy based imaging, and adherence to physician recommendations by more accurate lesion classification for risk prediction of future malignancy. Clinical implications: This project focuses on accurate risk stratification (via quick far field blood test) and proposes an adjunct approach (fluorescent mucin antibody visualization of polyps in high-risk patients) for identifying malignant polyps, the hidden culprits for 15-30% colon cancer. Furthermore, tumor-specific antibodies conjugated to near infrared (NIR) fluorophores that label CRC and liver metastases will enable successful fluorescence-guided surgery (FGS). Due to the utilization of unique imaging technology for early and accurate detection of premalignant polyps and CRC, the present project and can significantly affect management of CRC patients.

项目摘要摘要 CMA：标记辅助预防和风险分层（MAPRS）：粘蛋白特征及其分子 成像以早期检测到本文的结直肠癌，这是一组协作功绩审查申请 （CMA）旨在提高癌症的精确管理，尤其是专注于标记辅助预防 大结肠癌（CRC）的风险分层（MAPR），这是美国第三大癌症， 在退伍军人中占所有癌症的9.5％。筛查结肠镜检查已成为 迄今为止，对CRC的最有效的救生干预措施，其成功受到了易用性和 下降成本压力。此外，CRC，局部和远处复发的患者的Dospite高R0切除率 仍然是一个重大问题，已被认为高达40％。拟议的CMA旨在解决 这些局限性并严重破坏CRC预防，检测，风险分层和精确处理 通过推进MAPR。这些项目包括以下内容。 CMA1旨在增强人工智能 预防结肠直肠癌的内窥镜检查。 CMA2计划检查基于粘蛋白的标记以改进 内窥镜检测，切除，组织学分类和恶性结肠息肉的监测 （无链锯齿状腺瘤/息肉和腺瘤）并检查其临床实用性作为筛查的辅助功能 结肠镜检查。 CMA3提议验证组织和基于血液的组合生物标志物面板，源自 功能途径特异性研究，以改善结肠癌的早期检测并分层种群 根据他们发展CRC的风险。最后，CMA4计划检查基因组和/或大细胞药物 使用患者肿瘤丢弃的反应分析，并为证据开发片片平台 - 基于CRC的精确治疗策略。这些CMR彼此内在地链接 外部与VA结直肠癌细胞基因组学联盟（VA4C）外部，以最大程度地提高协同作用并确保 成功。理由：CRC的终生发展风险为5％，是最常见的癌症， 与癌症有关的第二个主要原因。筛查期间结肠镜检查的息肉切除术显着 降低了事件和整体死亡率。此外，即使在广泛使用筛查结肠镜检查之后， 普遍的右侧CRC发生了一个年龄调整的事件和死亡率。其中的很大比例 来自无缝脑腺瘤/息肉（SSA/PS）的肿瘤，这些肿瘤在初始期间未被发现 结肠镜检查。此外，只有40％的CRC在早期被诊断出，部分原因是缺乏合规性 以及更常见测试的低灵敏度和特异性，包括粪便隐匿性血液检查和阴险 （无症状）局部疾病的性质。我们的初步数据表明各种粘蛋白的表达改变了 在CRC进展过程中，以异常定位和糖基化和差异表达为特征。 根据初步研究和诊断中确定的差距，我们假设是基于血清的 基于表达改变和粘蛋白糖基化的组合生物标志物面板将用作强大的 结肠镜检查的辅助性，将提高监视效率，基于内窥镜检查的成像和遵守 医师通过更准确的病变分类提出建议，以预测未来恶性肿瘤的风险。 临床意义：该项目侧重于准确的风险分层（通​​过快速的远处血液测试）和 提案一种辅助方法（高危患者中息肉的荧光粘蛋白抗体可视化） 鉴定出恶性息肉，是15-30％结肠癌的隐藏罪魁祸首。此外，肿瘤特异性抗体 标记CRC和肝转移的近红外（NIR）荧光团将成功 荧光引导手术（FGS）。由于利用了独特的成像技术来早日准确 检测息肉前息肉和CRC，目前的项目，可以显着影响CRC的管理 患者。