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发病机制，并使这些疾病的分子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。报道了一项关于血清细胞因子作为反应和生存标志的纵向研究。 基因芯片确定的候选基因的功能已被检测后，过表达或抑制的肿瘤与显性的负性结构或RNAi已成为最近的研究，以确定潜在的分子治疗的目标。Egr-1转录因子在肝细胞生长因子诱导的血管生成因子PDGF和VEGF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受体是重要信号通路和基因程序的上游激活物。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。报道了该药对核因子-kB和靶基因的分子作用以及临床毒性和反应的研究。

The purpose of this project is to elucidate the molecular pathogenesis of squamous cell neoplasms of the upper aerodigestive tract, and to enable the development of approaches for molecular 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. A longitudinal study of serum cytokine factors as markers of response and survival was reported. The function of candidate genes identified by microarray have been examined following overexpression or inhibition by transfection of tumors with dominant negative constructs or RNAi has been the subject of recent investigations to identify potential targets for molecular therapy. The role of Egr-1 transcription factor in Hepatocyte Growth Factor-induced expression of angiogenic factors PDGF 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 important signal pathways and gene programs. 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. A study of the molecular effects of the drug on NF-kB and target genes and clinical toxicity and response was reported.