Targeting TEMs in Preclinical Tumor Models

临床前肿瘤模型中的靶向 TEM

• 批准号: 7592773
• 负责人: bradley d st croix
• 金额: $ 29.89万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592773
• 关键词: Antibodies; Biodistribution; Blood Vessels; Cell surface; Development; Endothelial Cells; Extracellular Domain; Growth; Human; Injection of therapeutic agent; Label; Modeling; Molecular Weight; Monitor; Mus; Neoplasm Metastasis; Pharmaceutical Preparations; Property; Proteins; Sensitivity and Specificity; Solid Neoplasm; Testing; Tumor Cell Line; Tumor Markers; angiogenesis; cancer therapy; mouse model; novel; pre-clinical; translational study; tumor

The development of new blood vessels, or angiogenesis, is essential for the growth and metastasis of most solid tumors. Targeting the endothelial cells that line tumor blood vessels is a promising anticancer strategy. We have recently identified several cell surface tumor endothelial markers (TEMs) that are conserved in both mouse and humans and that represent potentially useful targets for anticancer therapy. To determine whether these TEMs are in fact useful targets, we will begin translational studies using transplantable tumor models in mice. To target cell surface TEMs, we will develop antibodies recognize native TEM proteins on the cell surface of both mouse and human tumor vessels. We will begin our studies by attempting to target TEM8 and CD276, but later on may also attempt to target other cell surface TEMs such as TEM1, TEM5 or TEM7. Initial studies will involve labeling the antibodies with various markers that will allow us to monitor biodistribution following injection into tumor bearing mice. Subsequently, antibodies with the best sensitivity and specificity will be tested for their tumoricidal properties in preclinical mouse models and, if necessary, may be conjugated to small molecular weight drugs.

新血管的发育或血管生成对于大多数实体瘤的生长和转移至关重要。针对肿瘤血管内皮细胞是一种有前途的抗癌策略。我们最近发现了几种细胞表面肿瘤内皮标记物（TEM），它们在小鼠和人类中都是保守的，并且代表了抗癌治疗的潜在有用靶点。为了确定这些 TEM 是否确实是有用的靶标，我们将开始使用小鼠可移植肿瘤模型进行转化研究。为了靶向细胞表面 TEM，我们将开发识别小鼠和人类肿瘤血管细胞表面天然 TEM 蛋白的抗体。我们将首先尝试以 TEM8 和 CD276 为目标进行研究，但随后也可能尝试以其他细胞表面 TEM 为目标，例如 TEM1、TEM5 或 TEM7。初步研究将涉及用各种标记物标记抗体，这将使我们能够监测注射到荷瘤小鼠体内后的生物分布。随后，将在临床前小鼠模型中测试具有最佳敏感性和特异性的抗体的杀肿瘤特性，并且如有必要，可以将其与小分子量药物缀合。