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）是美国第三大癌症，占所有癌症的 9.5% 退伍军人中的癌症。筛查结肠镜检查期间的息肉切除术显着 降低了结直肠癌的发病率和相关患者的死亡率。然而，尽管 显着进展，结直肠癌风险降低仍然次优，特别是在相关方面更差 CRC 发生在右结肠。尽管内窥镜检查的质量指标集中于 改进标准腺瘤的检测，但之间缺乏一致性 传统腺瘤检出率和无蒂锯齿状息肉下划线可视化能力 需要辅助方法。此外，尽管 CRC 患者的 R0 切除率很高， 局部和远处复发仍然是一个重大问题，据报道高达 40%。这 肿瘤的完全切除对于患者的预后至关重要。我们和其他人已经证明 Claudin-1 (CLDN-1) 是一种紧密连接 (TJ) 蛋白，在结直肠癌 (CRC) 中表达增加 以阶段特定的方式，并且在结肠癌进展期间高度上调，并且 转移。多项研究进一步验证了 Claudin-1 结肠癌的因果作用 体外和体内的进展和转移。简而言之，CLDN1表达在一个阶段中增加 特定方式和上调的 CLDN1 表达是癌前 SSA/P 的特征 腺瘤和结直肠癌转移。值得注意的是，在我们的研究中，9 名转移患者中有 8 名来自 原位异种移植物 (PDOX) 表现出高 CLDN1 表达。我们进一步证明了 使用抗体引导成像清楚地与 NIR 荧光团缀合的抗 CLDN1 抗体 标记的肿瘤和肝转移瘤能够成功进行荧光引导手术（FGS）。 CLDN1 荧光肽检测 CRC 腺瘤的类似能力已由 另一个实验室。综上所述，我们假设术中使用 CLDN-1 靶向近端药物 红外荧光 (NIRF) 成像探针将改善高风险癌前病变的检测 腺瘤和结直肠癌转移，并提高其切除术。对于这个假设，我们提出 以下具体研究：具体目标 1：综合、表征和执行预 与 NIR 荧光团缀合的 CLDN-1 抗体的临床安全性评估。抗体染料 结合比提供最大的肿瘤信号、最小的短期和长期组织保留， 临床前研究将确定最低毒性。具体目标 2：评估 CLDN-1靶向成像探针在息肉和结直肠癌中的临床前和临床疗效 转移。 CLDN-1-NIRF 探针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从腺瘤和转移性肿瘤组织中获取样本。 CRC 进展关键过程中涉及的关键分子的表征 开发新的早期检测和治疗方法不仅会减少患者 VA-CRC 患者的死亡率，但也将有助于减轻相关的经济负担 退伍军人管理局。使用成像技术的临床前研究的结果 准确检测/切除癌前息肉和结直肠癌将严重影响 CRC 患者的管理。成功实现学习目标将为您铺平道路 用于迫切需要的新型成像探针以改进检测的 I 期临床试验， CRC 及其高风险前驱病变的切除和治疗。