Molecular Specialization of Tumor Lymphatics

描述（申请人提供）：肿瘤内部和周围的淋巴管是淋巴转移的关键决定因素。这项研究将为肿瘤治疗通过淋巴途径的全身输送提供工具。由申请人实验室开发的基于肽库的血管靶向，将用于分析肿瘤发生过程中淋巴血管的分子变化。在许多肿瘤类型和肿瘤发展阶段特异性识别淋巴的肽将被分离出来。筛选的设计将有利于多肽在一系列肿瘤中识别淋巴，而不是对单个肿瘤模型进行选择性。这些和已经存在的淋巴归巢肽的特异性将通过测试肽与小鼠和人类患者的正常组织和癌组织的结合来确定。最有希望的肽的靶分子（“受体”）将被确定，抗体将针对受体制备。如上所述鉴定和表征的肽，以及针对其受体制备的抗体，将测试它们对淋巴管和肿瘤生长的影响，以及它们将肽-药物或抗体药物偶联物传递到恶性前病变和恶性病变的能力。这种方法专门针对那些可能不容易通过血液循环进入的区域进行治疗。破坏肿瘤内部和周围的淋巴管以及邻近的肿瘤细胞可能对减少淋巴转移特别有效。从这些实验中产生的有希望的化合物将在临床前癌症模型中进行测试，以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.