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: 10412910
• 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/10412910
• 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; KRASG12D; 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; 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; efficacy evaluation; 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; risk prediction; risk stratification; 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.

项目概要摘要 CMA：标记辅助预防和风险分层 (MAPRS)：粘蛋白特征及其分子 用于早期检测结直肠癌的成像在此，一组协作的优点审查应用程序 (CMA) 旨在推进癌症的精准管理，特别关注标记物辅助预防 结直肠癌 (CRC) 的风险分层 (MAPRS)，结直肠癌是美国第三大癌症 占退伍军人所有癌症的 9.5%，而结肠镜检查可能已成为预防癌症的方法。 迄今为止针对结直肠癌最有效的救生干预措施，其成功受到易用性和 此外，尽管 CRC 患者的 R0 切除率较高，但局部和远处复发。 仍然是一个重大问题，高达 40% 的人认为拟议的 CMA 旨在解决这一问题。 这些限制并显着扰乱了 CRC 的预防、检测、风险分层和精准治疗 通过推进 MAPRS，CMA1 旨在开发人工智能增强型。 CMA2 计划检查基于粘蛋白的标记物以改善结直肠癌预防。 癌前结肠息肉的内镜检测、切除、组织学分类和监测 （无蒂锯齿状腺瘤/息肉和腺瘤）并检查其作为筛查辅助手段的临床效用 CMA3 提议验证源自组织和血液的组合生物标志物组。 功能途径特异性研究，以改善结肠癌的早期检测并对人群进行分层 最后，CMA4 计划检查基因组和/或细胞组药物。 使用患者的肿瘤丢弃物进行反应分析，并开发一个肿瘤芯片平台，以实现证据- 基于 CRC 的精准治疗策略，这些 CMR 之间有着内在的联系。 外部与 VA 结直肠癌细胞基因组学联盟 (VA4C) 合作，以最大限度地发挥协同作用并确保 成功理由：结直肠癌的终生发生风险为 5%，是第三大常见癌症，也是第三大常见癌症。 癌症相关死亡的第二个主要原因是结肠镜检查期间息肉切除术有显着影响。 此外，即使在广泛使用筛查性结肠镜检查之后，也降低了发病率和总体死亡率。 普遍存在的右侧结直肠癌的发病率和死亡率与年龄有关，其中大部分是右侧结直肠癌。 肿瘤由无蒂锯齿状腺瘤/息肉 (SSA/Ps) 产生，在初始阶段未被发现 此外，只有 40% 的 CRC 能够在早期得到诊断，部分原因是缺乏依从性。 以及更常见测试的低敏感性和特异性，包括粪便潜血测试和隐匿性测试 我们的初步数据表明各种粘蛋白的表达（无症状）。 在 CRC 进展期间，其特征是异常定位、糖基化和差异表达。 根据初步研究和已确定的诊断差距，我们认为基于血清 基于粘蛋白表达和糖基化改变的组合生物标志物组将作为一个强大的 结肠镜检查的辅助手段，将提高监测效率、基于内窥镜的成像以及遵守 医生建议通过更准确的病变分类来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​​过快速远场血液测试）和 提出了一种辅助方法（高危患者息肉的荧光粘蛋白抗体可视化） 识别恶性息肉，这是 15-30% 结肠癌的隐藏罪魁祸首。此外，还可以识别肿瘤特异性抗体。 与标记 CRC 和肝转移的近红外 (NIR) 荧光团结合将能够成功 荧光引导手术（FGS）由于利用独特的成像技术实现早期和准确。 癌前息肉和结直肠癌的检测，本项目可以显着影响结直肠癌的管理 患者。