Molecular Specialization of Tumor Lymphatics

描述（由申请人提供）：肿瘤内和周围的淋巴管是淋巴转移的关键决定因素。本研究将提供通过淋巴途径全身递送肿瘤治疗的工具。 在申请人的实验室中开发的基于肽库的血管靶向将用于描绘肿瘤发生期间淋巴管系统中的分子改变。将分离在许多肿瘤类型和肿瘤发展阶段中特异性识别肿瘤抑制剂的肽。筛选的设计将有利于识别一系列肿瘤中的代谢物的肽，而不是对单个肿瘤模型具有选择性。这些和已经存在的淋巴归巢肽的特异性将通过测试肽与来自小鼠和人类患者的正常和癌组织的结合来确定。 将识别最有希望的肽的靶分子（“受体”），并针对这些受体制备抗体。将测试如上所述鉴定和表征的肽和针对其受体制备的抗体对淋巴管和肿瘤生长的作用，以及它们将肽-药物或抗体药物缀合物递送至癌前病变和恶性病变的能力。这种方法专门针对治疗可能不容易通过血液循环到达的区域。 破坏肿瘤内和周围的淋巴管沿着邻近的肿瘤细胞可以特别有效地减少淋巴转移。从这些实验中出现的有前途的化合物将在临床前癌症模型中进行测试，用于治疗癌症和预防转移。

DESCRIPTION (provided by applicant): Lymphatic vessels in and around tumors are a key determinant in lymphatic metastasis. This study will provide tools for systemic delivery of tumor treatments through the lymphatic route. Peptide library-based vascular targeting, developed in the applicant's laboratory, will be used to profile molecular alterations in the lymphatic vasculature during tumorigenesis. Peptides that specifically recognize the lymphatics in a number of tumor types and stages of tumor development will be isolated. The design of the screening will favor peptides that recognize the lymphatics in a range of tumors, rather than being selective for an individual tumor model. The specificity of these and already existing lymphatic homing peptides will be ascertained by testing peptide binding to normal and cancerous tissues from mice and from human patients. The target molecules ('receptors') for the most promising peptides will be identified, and antibodies will be prepared against the receptors. The peptides identified and characterized as described above, and antibodies prepared against their receptors, will be tested for their effects on lymphatic vessels and tumor growth, and their ability to deliver peptide-drug or antibody drug conjugates to pre-malignant and malignant lesions. This approach specifically targets the treatments to areas that may not be readily accessible through the blood circulation. Destroying the lymphatic vessels in and around the tumor along with the adjacent tumor cells may be particularly effective in reducing lymphatic metastasis. Promising compounds emerging from these experiments will be tested in pre-clinical cancer models for treatment of cancer and prevention of metastasis.