Molecular Therapy Of Neoplasms Affecting Human Communication

影响人类交流的肿瘤的分子治疗

• 批准号: 7593327
• 负责人: CARTER VAN WAES
• 金额: $ 233.9万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593327
• 关键词: Affect; Apoptosis; Bioinformatics; Biological Assay; Biology; Bortezomib; Candidate Disease Gene; Cell Line; Cell Survival; Cetuximab; Cisplatin; Collaborations; Communication; Development; Disease; Dominant-Negative Mutation; Dose; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Gene Expression; Genes; Genome; Growth; Growth Factor; Head and Neck Squamous Cell Carcinoma; Histones; Human; Hypotension; IV Fluid; Immune; Malignant Epithelial Cell; Malignant Neoplasms; Michigan; Modeling; Molecular; Molecular Target; Mus; NF-kappa B; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Patients; Proteasome Inhibitor; Protein Overexpression; Protein p53; Proteomics; Purpose; RNA Interference; Radiation therapy; Recurrence; Reporting; Resistance; Role; Salivary; Schedule; Signal Transduction Pathway; Small Interfering RNA; Specialized Program of Research Excellence; Squamous Cell Neoplasms; Systems Biology; TP53 gene; Therapeutic; Transactivation; Transcription factor genes; Transfection; Treatment Protocols; Universities; Upper Aerodigestive Tract Neoplasms; casein kinase II; cytokine; cytotoxic; improved; lyt-10 protein; malignant oropharynx neoplasm; malignant phenotype; multicatalytic endopeptidase complex; neoplasm therapy; outcome forecast; partial response; programs; response; tumor; tumor progression

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 head and neck squamous cell carcinoma (HNSCC) cell line models have been developed and used to identify genes that are differentially expressed with tumor progression, using molecular and immune assays. Systems biology and bioinformatic analyses approaches are being used to identify gene programs and pathways involved in development of HNSCC. 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. Aim 1 Progress. We have obtained evidence that IKK1 (IKKalpha)and IKK 2 (IKKbeta) both contribute to activation of NF-kappaB, and identified a role for protein kinase CK2 in activation(Yu et al., Cancer Res., 2006; Van Waes, Clin Cancer Res. 2007). Studies are underway to determine if classical (IKK1/2 NF-kappaB1) and alternative (IKK1 NF-kappaB2) pathways are activated and contribute to gene expression and malignant phenotype of HNSCC, and may be inhibited by known and newly developed agents. Aim 2 Progress. NF-kappaB and p53 status have been implicated in expression of heterogeneous and common gene expression programs in HNSCC (Yan et al, Genome Biology, 2007). These signatures and pathway alterations have been associated with differences in prognosis. The expression and function of these candidate genes and pathways identified by microarray are being examined following overexpression or inhibition by transfection of tumors with dominant negative constructs or RNAi. The contribution of NF-kappaB to resistance to apoptosis and histone deacetylases, and effect of siRNA and proteasome inhibitor bortezomib to sensitize HNSCC was reported (Duan et al, Mol Cancer Therapeutics, 2007). Aim 3 Progress. In collaboration with the NCI Specialized Program of Research Excellence at University of Michigan, the potential of NF-kappaB regulated cytokines and growth factors to serve as proteomic markers of response, recurrence and survival was demonstrated in patients with oropharyngeal cancer following cisplatin and radiation therapy (Allen et al, Clin Cancer Res, 2007). An NIDCD/NCI trial of proteasome inhibitor bortezomib with reirradiation for patients with recurrent HNSCC is ongoing. A scheduled treatment break and IV fluid support was found to reduce hypotension obnserved in some patients, enabling dose escalation from 0.6 to 0.9 mg/m2. Five of seventeen patients treated at the initial dose level with different schedules have shown partial responses. A study combining bortezomib with Epidermal Growth Factor Receptor inhibitor cetuximab is under development.

本研究的目的是阐明上消化道鳞状细胞肿瘤的分子发病机制，并促进这些疾病的分子治疗方法的发展。人类和小鼠头颈部鳞状细胞癌（HNSCC）细胞系模型已经开发出来，并使用分子和免疫分析来鉴定肿瘤进展中差异表达的基因。系统生物学和生物信息学分析方法被用于识别参与HNSCC发展的基因程序和途径。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。