Molecular Therapy Of Neoplasms Affecting Human Communica

本项目的目的是阐明上呼吸道鳞状细胞肿瘤的分子和免疫发病机制，并使这些疾病的分子和免疫治疗方法的发展成为可能。人和小鼠鳞状细胞癌细胞系模型已经被开发出来，并用于使用分子和免疫分析来识别与肿瘤进展相关的差异表达基因。促炎症细胞因子、相关信号转导通路分子和即刻早期转录因子基因随着肿瘤的进展而过度表达或激活，并与侵袭性生长和转移有关。这些候选基因在通过转染具显性负结构的肿瘤后的过度表达或抑制后的功能一直是最近确定分子和免疫治疗的潜在靶点的研究的主题。转录因子在血管生成因子IL-8和血管内皮生长因子表达中的作用已经阐明。肝细胞生长因子/MET受体、表皮生长因子受体和IL-6受体是这些信号通路和细胞因子的上游激活因子。对核因子-kB作用的识别导致了一种蛋白酶体抑制剂的临床研究，该抑制剂可以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. The role of transcription factors in expression of angiogenic factors IL-8 and VEGF has been elucidated. Hepatocyte Growth Factor/ MET receptor, Epidermal Growth Factor Receptor and the IL-6 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.