Molecular Therapy Of Neoplasms Affecting Human Communica

本项目的目的是阐明上呼吸消化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。已经开发了人和鼠鳞状细胞癌细胞系模型，并使用分子和免疫测定来鉴定随着肿瘤进展而差异表达的基因。促炎细胞因子、相关信号转导通路分子和即刻早期转录因子基因已被证明随着肿瘤进展而过表达或激活，并且与侵袭性生长和转移相关。报告了一项血清细胞因子作为反应和生存标志物的纵向研究。 通过微阵列鉴定的候选基因的功能已经在通过用显性负性构建体转染肿瘤的过表达或抑制后进行了检查，或者RNAi已经成为最近研究的主题，以鉴定用于分子治疗的潜在靶标。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表达中的作用已被阐明。肝细胞生长因子/ MET受体、表皮生长因子受体和IL-6受体已被鉴定为重要信号通路和基因程序的上游激活剂。对NF-kB作用的鉴定导致了对蛋白酶体抑制剂的临床研究，该蛋白酶体抑制剂抑制肿瘤生长和血管生成并使头颈癌对辐射敏感。本文报道了该药对NF-κ B和靶基因的分子效应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.