Modulation of Head and Neck Cancer by Protein Kinase C

描述(申请人提供)：头颈部鳞状细胞癌(SCCHN)通常过度表达表皮生长因子受体(EGFR)，与不良预后、治疗失败和缩短生存期有关。蛋白激酶C酶(PKCs)也参与了生长控制，特别是作为EGF信号的中介。最近，我们已经证明了非典型的蛋白激酶C亚型PKC Zeta是EGF诱导头颈部癌细胞MAPK激活所必需的。PKC Zeta还与p70 S6激酶和生存因子核因子kappaB(NF-kappaB)的激活有关，我们发现抑制PKC Zeta可以促进头颈部肿瘤细胞的凋亡。最后，我们已经证明了经典和新型PKC的一般抑制剂在体外和体内对SCCHN具有细胞毒性，但具体的PKC亚型尚未确定。本提案旨在确定调控导致SCCHN生长和存活的信号通路的PKC亚型，并确定PKC抑制剂作为治疗SCCHN的潜在疗效。具体地说，我们计划：1)确定PKC在头颈部鳞状细胞癌临床试验期间收集的肿瘤和正常组织中表达的性质；2)鉴定PKC同工酶在EGF和血清刺激头颈部肿瘤细胞中的作用；3)测试PKC抑制剂单独或联合放射、EGFR抑制剂或肿瘤坏死因子-α对头颈部肿瘤细胞凋亡的影响；以及4)确定PKC靶向药物在体内对头颈部肿瘤细胞的影响。

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.