Molecular Targeted Imaging in Colon Cancer

描述（由申请人提供）：依赖于早期、特异性和充分理解的分子生物标志物成像的结直肠癌诊断程序存在未满足的需求。我们假设异常表达的血管内皮生长因子（VEGFR）受体是结直肠癌病变分子成像的特别有吸引力的生物标志物。这一假说是基于证据充分的VEGFR表达增强，在结直肠癌进展的早期就开始了，并与血管生成有关。我们最近描述了用于荧光VEGFR成像的第一种可内化示踪剂scVEGF/Cy，其是基因工程改造的单链VEGF，用近红外荧光染料Cy5.5位点特异性标记。我们发现肿瘤和活化的宿主血管系统中的内皮细胞通过VEGF介导的内吞作用结合并内化scVEGF/Cy，导致Cy5.5在肿瘤区域中选择性和持续性积聚。因此，Cy5.5标记的细胞可以在整个动物、收获的荷瘤器官和组织学组织切片中成像。我们的初步研究结果表明，scVEGF/Cy选择性和特异性地积累在大肠癌的基因工程小鼠模型APC（Delta14/+）的结肠和小肠肿瘤病变的内皮细胞中。这些发现表明使用scVEGF/Cy用于结直肠病变的早期荧光检测的可行性，并导致I期的焦点计划。在与J.巴顿博士（美国）的合作下，亚利桑那州），我们提出以下具体目标：具体目标#1。通过VEGF介导的荧光成像优化结直肠病变的检测。具体目标#2。目的探讨scVEGF/Cy示踪剂用于结直肠病变早期诊断的可行性。具体目标#3在Apc（Delta14/+）小鼠中评价scVEGF/Cy示踪剂的荧光结肠镜检查。实现这些特定目标将验证VEGFR作为荧光结肠镜检查的分子生物标志物，并建立scVEGF/Cy II期临床开发的可行性。我们建议测试的可行性，使用有针对性的分子成像与荧光示踪剂的早期检测结直肠癌。示踪剂将靶向VEGF受体，其在肿瘤血管系统中的增强表达和内化示踪剂的能力使其对于诊断成像非常有吸引力。在该项目的第一阶段，我们将联合收割机与SibTech公司首席研究员开发的一种新型靶向荧光示踪剂相结合，和一种由我们在亚利桑那大学的合作者开发的用于荧光内窥镜检查的新型探针，并在一种新型的自发性结直肠肿瘤基因工程小鼠模型中测试它们用于检测早期癌性病变。该项目第一阶段的成功将导致该项目第二阶段临床开发用于前列腺癌早期诊断的新成像示踪剂。

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.