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）通常过度表达表皮生长因子受体（EGFR），与预后不良、治疗失败和生存期缩短有关。蛋白激酶C酶（PKCs）也与生长控制有关，特别是作为EGF信号传导的介质。最近，我们已经证明了非典型蛋白激酶C异构体PKC zeta是EGF诱导的头颈部癌细胞系中MAPK激活所必需的。PKC zeta也参与了p70s6激酶和存活因子核因子κ B （nf - κ B）的激活，我们已经证明PKC zeta的抑制促进了头颈部肿瘤细胞的凋亡。最后，我们已经证明，在体外和体内，经典和新型PKC的一般抑制剂对scchn具有细胞毒性，但尚未确定具体的PKC亚型。本研究旨在确定PKC亚型，该亚型调节导致SCCHN生长和存活的信号通路，并确定PKC抑制剂作为治疗SCCHN的药物的潜在功效。具体而言，我们计划：1)确定PKC在头颈部鳞状细胞癌临床试验中收集的人类肿瘤和正常组织中的表达性质；2)表征PKC同工酶在头颈部肿瘤细胞EGF和血清刺激中的作用；3)检测PKC抑制剂单独或联合放疗、EGFR抑制剂或tnf - α对头颈部肿瘤细胞凋亡的影响；4)确定PKC靶向药物在体内对头颈癌的作用。

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.