Targeting TEMs in Preclinical Tumor Models

临床前肿瘤模型中的靶向 TEM

• 批准号: 8763139
• 负责人: bradley d st croix
• 金额: $ 30.06万
• 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/8763139
• 关键词: Angiogenesis Inhibitors; Antibodies; Antineoplastic Agents; Binding; Biological Markers; Blood; Blood Vessels; Cell Line; Cell surface; Cells; Development; Endothelial Cells; Extracellular Domain; Growth; Human; Life; Modeling; Molecular Weight; Monitor; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Pharmaceutical Preparations; Property; Proteins; Sensitivity and Specificity; Solid Neoplasm; Testing; angiogenesis; cancer therapy; mouse model; neutralizing antibody; novel; pre-clinical; response; screening; 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. Initial studies will involve screening the antibodies for their ability to bind live cells which express the target TEM. Whenever possible, secondary screens to identify neutralizing antibodies will be employed. 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. Antibodies will also be tested for their ability to detect soluble TEMs in the blood. Combinations of our novel anti-angiogenics with conventional anti-cancer agents will also be tested.

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。初步研究将包括筛选抗体结合表达目标 TEM 的活细胞的能力。只要有可能，将采用二次筛选来鉴定中和抗体。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。还将测试抗体检测血液中可溶性 TEM 的能力。我们的新型抗血管生成药物与传统抗癌药物的组合也将进行测试。