Novel Tools for Colon Cancer Detection and Therapy

结肠癌检测和治疗的新工具

• 批准号: 10480318
• 负责人: Michael Bouvet
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480318
• 关键词: Adenocarcinoma; Adjuvant; American; Antibodies; Biodistribution; Biology; Clinical; Colon; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colonoscopy; Colorectal Cancer; Consensus; Detection; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Distant; Drug Kinetics; Dyes; Early Diagnosis; Endoscopy; Evaluation; Excision; Exhibits; Female; Financial Hardship; Fluorescence; Fluorescent Probes; Frequencies; General Population; Goals; Image; Image-Guided Surgery; Imaging technology; In Vitro; Incidence; KRASG12D; Label; Laboratories; Laparoscopy; Lesion; Malignant - descriptor; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Modality; Modeling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient imaging; Patient-Focused Outcomes; Patients; Peptides; Phase I Clinical Trials; Polypectomy; Polyps; Population; Process; Productivity; Proteins; Quality of life; Recurrence; Recurrent Malignant Neoplasm; Reporting; Research; Risk Reduction; Role; Sampling; Sensitivity and Specificity; Signal Transduction; Societies; Surgical margins; Therapeutic; Tight Junctions; Time; Tissues; Toxic effect; Tumor Tissue; United States Department of Veterans Affairs; Veterans; Visualization; Xenograft Model; Xenograft procedure; adenoma; antibody conjugate; biomarker identification; cancer invasiveness; cancer recurrence; cancer surgery; cancer therapy; claudin-1 protein; clinical efficacy; colon cancer cell line; colon cancer patients; colon cancer progression; colon cancer screening; colorectal cancer metastasis; colorectal cancer progression; colorectal cancer risk; colorectal cancer screening; detection sensitivity; efficacy evaluation; ex vivo imaging; fluorescence imaging; fluorescence-guided surgery; fluorophore; high risk; image guided; imaging probe; improved; in vivo; male; metastatic colorectal; mortality; mouse model; novel; pre-clinical assessment; preclinical efficacy; preclinical safety; preclinical study; premalignant; screening; subcutaneous; success; targeted imaging; tool; tumor

Colorectal cancer (CRC) is the third major cancer in the USA and accounts for 9.5% of all the cancers among the Veterans. Polypectomy during screening colonoscopy has significantly reduced both the CRC incidence and associated patient mortality. However, despite the significant progress, the CRC risk reduction remains suboptimal and specifically worse in relation to CRC arising in the right colon. Although quality metrics in endoscopy have focused on improving detection of standard adenomas, there is a lack of concordance between the conventional adenoma detection rate and ability to visualize sessile serrated polyps underscoring the need for adjuvant approaches. 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%. The complete resection of tumor is critical to patient outcomes. We and others have shown that Claudin-1(CLDN-1), a tight junction (TJ) protein, expression increases in colorectal cancer (CRC) in stage specific manner, and is highly upregulated during colon cancer progression and metastasis. Several studies have further validated a causal role of Claudin-1 colon cancer progression and metastasis in vitro and in vivo. In brief, CLDN1 expression increases in a stage specific manner and an upregulated CLDN1 expression characterizes both, pre-malignant SSA/P adenomas and CRC metastasis. Notably, in our study, 8 out of 9 metastatic patients derived orthotopic xenografts (PDOX) demonstrated high CLDN1 expression. We further demonstrated that using antibody-guided imaging anti-CLDN1 antibodies conjugated to NIR fluorophores clearly labeled tumor and liver metastases enabling successful fluorescence-guided surgery (FGS). Similar ability of CLDN1 fluorescent peptides for detection of CRC adenomas was reported by another lab. Taken together, we hypothesize that intraoperative use of CLDN-1-targeted near- Infrared fluorescent (NIRF) imaging probes will improve the detection of high-risk pre-malignant adenomas and CRC metastasis, and also improve their resection. To this hypothesis, we propose following specific studies: SPECIFIC AIM 1: To synthesize, characterize, and perform the pre- clinical safety evaluation of CLDN-1 antibodies-conjugated to NIR fluorophores. The antibody-dye conjugate ratio providing maximum tumor signal, minimum short and long-term tissue retention, and lowest toxicity will be established for pre-clinical studies. SPECIFIC AIM 2: Assessment of the pre-clinical and clinical efficacy of CLDN-1-targeted imaging probes in polyps and CRC metastasis. The clinical-guiding efficacy of CLDN-1-NIRF probes will also be validated in surgical samples from adenomas and metastatic tumor tissues using ex vivo imaging of patient tissues. Characterization of the key molecules involved in the processes critical for CRC progression to develop novel early detection and therapeutic approaches would not only decrease patient mortality among VA-CRC patients but will also help reduce associated financial burden for the Veterans Administration. The outcome from the preclinical studies using the imaging technology for accurate detection/resection of premalignant polyps and CRC will strongly impact the management of CRC patients. Successful accomplishment of the study goals will pave the path for a Phase-I clinical trial for urgently needed novel imaging probes for improved detection, resection, and management of the CRC and its high-risk precursor lesions.

结直肠癌（CRC）是美国的第三大癌症，占所有癌症的9.5%。 退伍军人中的癌症结肠镜检查中息肉切除术 降低CRC发病率和相关患者死亡率。但尽管 尽管取得了重大进展，但CRC风险降低仍不理想，特别是在相关方面更差。 大肠癌发生在右半结肠。尽管内窥镜检查的质量指标主要集中在 提高标准腺瘤的检出率， 传统腺瘤的检出率和无蒂锯齿状息肉的可视化能力强调了 需要辅助方法。此外，尽管CRC患者的R 0切除率很高， 局部和远处复发仍然是一个重要的问题，据报道高达40%。的 肿瘤的完全切除对患者的预后是至关重要的。我们和其他人已经证明， 紧密连接蛋白Claudin-1（CLDN-1）在结直肠癌（CRC）中的表达增加 以阶段特异性方式，并且在结肠癌进展期间高度上调， 转移一些研究进一步证实了Claudin-1结肠癌的因果作用 在体外和体内的进展和转移。简而言之，CLDN 1表达在一个阶段增加， 特异性方式和上调的CLDN 1表达表征了癌前SSA/P 腺瘤和CRC转移。值得注意的是，在我们的研究中，9例转移性患者中有8例 原位异种移植物（PDOX）显示高CLDN 1表达。我们进一步表明 使用与NIR荧光团缀合的抗体引导成像抗CLDN 1抗体， 标记的肿瘤和肝转移，使成功的荧光引导手术（FGS）。 CLDNl荧光肽用于检测CRC腺瘤的类似能力由Werner等人报道。 另一个实验室综上所述，我们假设术中使用CLDN-1靶向近端- 红外荧光（NIRF）成像探针将提高高风险癌前病变的检测 腺瘤和结直肠癌转移，并提高其切除率。对于这一假设，我们提出 以下具体研究：具体目标1：合成，表征，并进行预- 与NIR荧光团缀合的CLDN-1抗体的临床安全性评价。抗体染料 提供最大肿瘤信号、最小短期和长期组织保留的缀合物比率， 并且将为临床前研究确定最低毒性。具体目标2：评估 CLDN-1靶向成像探针在息肉和CRC中的临床前和临床疗效 转移CLDN-1-NIRF探头的临床指导功效也将在外科手术中得到验证。 使用患者组织的离体成像采集来自腺瘤和转移性肿瘤组织的样本。 表征参与CRC进展至癌症的关键过程的关键分子， 开发新的早期检测和治疗方法不仅可以减少患者 VA-CRC患者的死亡率，但也将有助于减少相关的经济负担， 退伍军人管理局。使用成像技术的临床前研究的结果 对于癌前息肉和CRC的准确检测/切除， CRC患者的管理。学习目标的成功实现将铺平道路 对于急需的用于改进检测的新型成像探针的I期临床试验， CRC及其高风险前驱病变的切除和管理。