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.

项目总结摘要 CMA：标记辅助预防和风险分层(MAPRS)：粘蛋白特征及其分子 成像用于结直肠癌的早期检测在这里，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，特别是注重标记物辅助预防 和结直肠癌的风险分层(MAPRS)，这是美国的第三大癌症， 占退伍军人所有癌症的9.5%。虽然筛查结肠镜检查已经成为可能 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 成本下行压力。此外，尽管结直肠癌患者的R0切除率很高，但局部和远程复发 这仍然是一个严重的问题，被引用的比例高达40%。拟议的CMA旨在解决 这些限制并严重扰乱了CRC的预防、检测、风险分层和精确治疗 通过推进MAPR。项目包括以下几个方面。CMA1旨在发展增强的人工智能 用于结直肠癌预防的内窥镜检查。CMA2计划检查基于粘蛋白的标志物以进行改进 大肠息肉癌前病变的内窥镜检查、切除、组织学分类及监测 (固有性锯齿状腺瘤/息肉和腺瘤)，并检查其作为筛查辅助手段的临床应用 结肠镜检查。CMA3建议验证基于组织和血液的组合生物标志物面板，源自 功能通路特异性研究，以提高结肠癌的早期检测和人群分层 根据他们患上结直肠癌的风险。最后，CMA4计划检查基因组和/或细胞药物 使用患者的肿瘤丢弃进行反应分析，并开发一个芯片上肿瘤平台，以获得证据- 基于对大肠癌的精准治疗策略。这些CMR彼此之间内在地联系在一起，并且 与VA结直肠癌细胞基因组学联盟(VA4C)进行外部合作，以最大限度地发挥协同作用并确保 成功。理论基础：结直肠癌的终生发展风险为5%，是第三种最常见的癌症， 癌症相关死亡的第二个主要原因。结肠镜下息肉切除术在筛查过程中有显著意义 降低了发病率和总死亡率。此外，即使在广泛使用筛查结肠镜检查后， 有一个年龄调整的发病率和死亡率的流行，右侧的癌。其中的主要比例 肿瘤发生于无柄锯齿状腺瘤/息肉(SSA/Ps)，在最初未被发现 结肠镜检查。此外，只有40%的CRC在早期阶段被诊断出来，部分原因是缺乏遵从性 以及更常见的测试的敏感性和特异性较低，包括粪便潜血测试和潜伏期 (无症状的)局部疾病的性质。我们的初步数据表明各种粘蛋白的表达发生了变化 在结直肠癌进展过程中，以异常定位、糖基化和差异表达为特征。 根据初步研究和已确定的诊断差距，我们假设血清是基于 基于粘蛋白表达和糖基化改变的组合生物标志物小组将成为一种强大的 作为结肠镜检查的辅助工具，将提高监视效率、基于内窥镜的成像，并符合 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，肿瘤特异性抗体 结合标记结直肠癌和肝转移的近红外(NIR)荧光团将使成功 荧光引导手术(FGS)。由于利用独特的成像技术进行早期和准确的 癌前息肉和结直肠癌的检测，目前的项目和可以显著影响结直肠癌的处理 病人。