Molecular Therapy Of Neoplasms Affecting Human Communication

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。人和小鼠头颈部鳞状细胞癌(HNSCC)细胞系模型已经建立，并用于利用分子和免疫分析来鉴定与肿瘤进展有关的差异表达基因。系统生物学和生物信息学分析方法正被用来确定参与HNSCC发展的基因程序和途径。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。 目标1进步。我们已经获得证据表明，IKK1(IKKalpha)和IKK2(IKKbeta)都有助于核因子-kappaB的激活，并确定了蛋白激酶CK2在激活中的作用(Yu等人，癌症研究，2006；Van Waes，临床癌症研究，2007)。目前正在进行研究，以确定经典通路(IKK1/2 NF-kappaB1)和替代通路(IKK1 NF-kappaB2)是否被激活，并与HNSCC的基因表达和恶性表型有关，并可能被已知和新开发的药物抑制。 目标2进步。核因子-kappaB和P53的状态与HNSCC中异质性和常见基因表达程序的表达有关(Yan等，基因组生物学，2007)。这些信号和通路改变与预后的不同有关。基因芯片确定的这些候选基因和途径的表达和功能正在通过转染具有显性负结构或RNAi的肿瘤过表达或抑制后进行检测。关于核因子-kappaB在抵抗细胞凋亡和组蛋白脱乙酰酶中的作用，以及siRNA和蛋白酶体抑制剂Bortezomib增敏HNSCC的作用已有报道(Duan等，Mol Cancer Treeutics，2007)。 目标3进步。在与密歇根大学NCI卓越研究专门计划的合作下，核因子-kappaB调节的细胞因子和生长因子作为顺铂和放射治疗后口咽癌患者反应、复发和生存的蛋白质组标志的潜力被证明(Allen等，临床癌症研究，2007年)。蛋白酶体抑制剂Bortezomib再照射治疗复发性HNSCC患者的NIDCD/NCI试验正在进行中。计划的治疗中断和静脉输液支持被发现可以减少一些患者观察到的低血压，使剂量从0.6毫克/平方米增加到0.9毫克/平方米。在以不同方案进行初始剂量水平治疗的17名患者中，有5名患者出现部分反应。一项将波特佐米与表皮生长因子受体抑制剂西妥昔单抗联合使用的研究正在进行中。

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.