Gene And Immunotherapy Of Neoplasms Affecting Human Comm

本项目旨在阐明上消化道鳞状细胞肿瘤的分子和免疫发病机制，并为这些疾病的分子和免疫治疗方法的发展奠定基础。人类和小鼠鳞状细胞癌细胞系模型已经被开发出来，并用于通过分子和免疫测定来识别肿瘤进展中差异表达的基因。促炎细胞因子、相关信号转导途径分子和即时早期转录因子基因在肿瘤进展过程中被过度表达或激活，并与侵袭性生长和转移有关。通过转染具有显性阴性结构的肿瘤，这些候选基因在过表达或抑制后的功能已成为最近研究的主题，以确定分子和免疫治疗的潜在靶点。在过去的一年中，转录因子NF-kB和AP-1在血管生成因子IL-8和VEGF表达中的作用已经被阐明。肝细胞生长因子/ MET受体、表皮生长因子受体和IL-1受体已被确定为这些信号通路和细胞因子的上游激活因子。NF-kB作用的鉴定导致了一项蛋白酶体抑制剂的临床研究，该抑制剂抑制肿瘤生长和血管生成，并使头颈部癌症对辐射敏感。

The purpose of this project is to elucidate the molecular and immune pathogenesis of squamous cell neoplasms of the upper aerodigestive tract, and to enable the development of approaches for molecular and immune therapy for these disorders. Human and murine squamous cell carcinoma cell line models have been developed and used to identify genes that are differentially expressed with tumor progression using molecular and immune assays. Proinflammatory cytokines, related signal transduction pathway molecules, and immediate early transcription factor genes have been shown to be overexpressed or activated with tumor progression, and are associated with aggressive growth and metastasis. The function of these candidate genes following overexpression or inhibition by transfection of tumors with dominant negative constructs has been the subject of recent investigations to identify potential targets for molecular and immune therapy. During the past year, the role of transcription factors NF-kB and AP-1 in expression of angiogenic factors IL-8 and VEGF has been elucidated. Hepatocyte Growth Factor/ MET receptor, Epidermal Growth Factor Receptor and the IL-1 Receptor have been identified as upstream activators of these signal pathways and cytokines. Identification of the role of NF-kB has led to a clinical study of a proteasome inhibitor which inhibits tumor growth and angiogenesis and sensitizes head and neck cancers to radiation.