Modulation of Head and Neck Cancer by Protein Kinase C

描述（由申请人提供）：头颈部鳞状细胞癌（SCCHN）通常过表达表皮生长因子受体（EGFR），其与预后不良、治疗失败和生存期缩短有关。蛋白激酶C酶（PKC）也参与生长控制，特别是作为EGF信号传导的介质。最近，我们已经证明，非典型蛋白激酶C亚型，PKC ζ，是必要的表皮生长因子诱导的MAPK活化头颈癌细胞系。PKC zeta还与p70 S6激酶和存活因子核因子κ B（NF-κ B）的活化有关，并且我们已经表明抑制PKC zeta促进头颈部肿瘤细胞的凋亡。最后，我们已经表明，一般抑制剂的经典和新的PKC细胞毒性SCCHN在体外和体内，但具体的PKC亚型负责尚未确定。本提案旨在确定PKC亚型，调节信号通路，导致SCCHN的生长和生存，并确定潜在的疗效的PKC抑制剂作为治疗剂治疗SCCHN。具体而言，我们计划：1）确定在头颈部鳞状细胞癌的临床试验期间收集的人肿瘤和正常组织中PKC表达的性质; 2）表征PKC同工酶在头颈部肿瘤细胞的EGF和血清刺激中的作用; 3）测试PKC抑制剂单独或与辐射、EGFR抑制剂或TNF-α组合对头颈部肿瘤细胞凋亡的作用;（4）PKC靶向药物对头颈癌的体内治疗作用。

DESCRIPTION (provided by applicant): Squamous cell carcinomas of the head and neck (SCCHN) generally overexpress epidermal growth factor receptors (EGFR) that have been linked to poor prognosis, treatment failure, and shortened survival. Protein kinase C enzymes (PKCs) have also been implicated in growth control, particularly as mediators of EGF signaling. Recently, we have demonstrated that the atypical protein kinase C isoform, PKC zeta, is necessary for EGF induced MAPK activation in head and neck cancer cell lines. PKC zeta has also been implicated in activation of p70 S6 kinase and the survival factor Nuclear Factor kappa B (NF-kappaB), and we have shown that inhibition of PKC zeta promotes apoptosis in head and neck tumor cells. Finally, we have shown that general inhibitors of classic and novel PKCs are cytotoxic to SCCHNs in vitro and in vivo, but the specific PKC isoforms responsible have not been identified. The present proposal seeks to identify the PKC isoforms that regulate signaling pathways that lead to SCCHN growth and survival, and to determine the potential efficacy of PKC inhibitors as therapeutic agents for the treatment of SCCHN. Specifically, we plan to: 1) Determine the nature of PKC expression in human tumor and normal tissues collected during clinical trials in squamous cell carcinoma of the head and neck; 2) Characterize the role of PKC isozymes in EGF and serum stimulation of head and neck tumor cells; 3) Test the effect of PKC inhibitors on apoptosis of head and neck tumor cells either alone or in combination with radiation, EGFR inhibitors, or TNF-alpha; and 4) Determine the effect of PKC targeted agents on head and neck cancer in vivo.