Molecular Targeted Imaging in Colon Cancer

结肠癌的分子靶向成像

• 批准号: 7405731
• 负责人: Joseph M Backer
• 金额: $ 16.29万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405731
• 关键词: Aberrant crypt foci; Animals; Area; Arizona; Binding; Biological Markers; Biological Process; C-terminal; Cancerous; Cells; Characteristics; Chemopreventive Agent; Clinical; Collaborations; Colon; Colon Carcinoma; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Columbidae; Complex; Computed Tomographic Colonography; Crohn' s disease; Detection; Development; Diagnostic; Diagnostic Imaging; Diagnostic Neoplasm Staging; Diagnostic Procedure; Distal; Early Diagnosis; Endocytosis; Endoscopy; Endothelial Cells; Engineering; Fluorescent Dyes; Fluorescent Probes; Genetically Engineered Mouse; Genus Cola; Gills; Goals; Harvest; Human; Image; Label; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Molecular Target; Monitor; Mus; Optics; Organ; Patients; Phase; Play; Preventive; Principal Investigator; Process; Role; Site; Small Intestinal Neoplasm; Small Intestines; Staging; Techniques; Testing; Tissues; Tracer; Tumor stage; Ulcerative Colitis; Universities; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; adenoma; angiogenesis; base; cancer diagnosis; colorectal cancer screening; density; improved; in vivo; innovation; molecular imaging; mouse model; novel; programs; receptor; research study; success; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): There is an unmet need in a diagnostic procedure for colorectal cancer that relies on imaging of an early, specific, and well-understood molecular biomarker. We hypothesized that abnormally expressed receptors for vascular endothelial growth factor (VEGFR) are particularly attractive biomarkers for molecular imaging of colorectal cancerous lesions. This hypothesis is based on well-documented enhanced expression of VEGFR that begins very early in colorectal cancer progression and is associated with angiogenesis. We have recently described the first internalizable tracer for fluorescent VEGFR imaging, scVEGF/Cy, which is a genetically engineered single-chain VEGF, site- specifically labeled with near-infrared fluorescent dye, Cy5.5. We found that endothelial cells in tumor and activated host vasculature bind and internalize scVEGF/Cy via VEGFR-mediated endocytosis, leading to selective and persistent accumulation of Cy5.5 in tumor area. As a result, Cy5.5-tagged cells can be imaged in whole animals, harvested tumor-bearing organs, and on histological tissue sections. Our preliminary results indicate that scVEGF/Cy selectively and specifically accumulates in endothelial cells in tumor lesions in colon and small intestines of genetically engineered mouse model APC(Delta14/+) of spontaneous colorectal cancer. These finding suggests the feasibility of using scVEGF/Cy for early fluorescent detection of colorectal lesions and lead to focus program for Phase I. In collaboration with Dr. J. Barton (U. Arizona) we propose the following Specific Aims: Specific Aim #1. To optimize detection of colorectal lesions via VEGFR-mediated fluorescent imaging. Specific Aim #2. To establish the feasibility of early detection of colorectal lesions with scVEGF/Cy tracer. Specific Aim #3. To evaluate fluorescent colonoscopy with scVEGF/Cy tracer in Apc(Delta14/+) mouse. Accomplishing these specific aims will validate VEGFR as a molecular biomarker for fluorescent colonoscopy and and establish the feasibility of clinical development of scVEGF/Cy in Phase II. We propose to test a feasibility of using targeted molecular imaging with fluorescent tracer for early detection of colorectal cancer. The tracer will be targeted to VEGF receptors, whose enhanced expression in tumor vasculature and ability to internalize the tracer make them very attractive for diagnostic imaging. In Phase I of the project we will combine a novel targeted fluorescent tracer developed by Principal Investigator at SibTech, Inc., and a novel probe for fluorescent endoscopy developed by our collaborator at The Arizona University, and test them for detection of early cancerous lesions in a novel genetically engineered mouse model of spontaneous colorectal tumor. The success of Phase I of this project will lead to clinical development of a new imaging tracer for early diagnostic of prostate cancer in Phase II of this project.

描述(申请人提供)：在结直肠癌的诊断程序中，有一个尚未满足的需求，它依赖于一个早期的、特异的和众所周知的分子生物标记物的成像。我们推测，血管内皮生长因子受体(VEGFR)的异常表达对于结直肠癌病变的分子成像是特别有吸引力的生物标志物。这一假说建立在已有文献记载的VEGFR表达增强的基础上，VEGFR在结直肠癌进展的早期就开始了，并与血管生成有关。我们最近描述了第一个用于荧光VEGFR成像的内在化示踪剂scVEGF/Cy，它是一种基因工程的单链血管内皮生长因子，用近红外荧光染料Cy5.5定点标记。我们发现，肿瘤中的内皮细胞和激活的宿主血管通过VEGFR介导的内吞作用结合和内化scVEGF/Cy，导致Cy5.5在肿瘤区域选择性和持续积聚。因此，Cy5.5标记的细胞可以在整个动物、收获的肿瘤器官和组织切片上成像。我们的初步结果表明，在自发性结直肠癌基因工程小鼠模型APC(Delta14/+)中，scVEGF/Cy选择性和特异性地聚集在肿瘤病变的结肠和小肠内皮细胞中。这些发现表明，将scVEGF/Cy用于大肠病变的早期荧光检测是可行的，并导致I期的焦点计划。我们与J.Barton博士(美国亚利桑那州大学)合作提出了以下具体目标：具体目标#1.通过VEGFR介导的荧光成像优化大肠病变的检测。具体目的#2.建立scVEGF/Cy示踪剂早期检测大肠病变的可行性。具体目的#3.应用scVEGF/Cy示踪剂对APC(Delta14/+)小鼠进行荧光结肠镜检查。这些特定目标的实现将验证VEGFR作为荧光结肠镜检查的分子生物标记物的有效性，并建立第二阶段scVEGF/Cy临床开发的可行性。我们建议测试靶向分子成像结合荧光示踪剂用于结直肠癌早期检测的可行性。该示踪剂将针对血管内皮生长因子受体，其在肿瘤血管中的增强表达和内化示踪剂的能力使其非常适合于诊断成像。在该项目的第一阶段，我们将结合SibTech，Inc.首席研究员开发的一种新型靶向荧光示踪剂，以及我们在亚利桑那大学的合作者开发的一种用于荧光内窥镜检查的新型探针，并在一种新的自发性结直肠肿瘤基因工程小鼠模型中对它们进行检测。该项目第一阶段的成功将导致该项目第二阶段用于前列腺癌早期诊断的新的成像示踪剂的临床开发。