TARGETING EGFR AND GPCR SIGNALING IN SCCHN

描述(申请人提供)：头颈部鳞状细胞癌(SCCHN)是通过控制细胞的基因的复杂遗传和表观遗传改变而发展起来的 增殖、细胞周期和细胞存活。一组经常改变表达的基因是生长因子及其受体的基因，包括表皮生长因子受体(EGFR)。G蛋白偶联受体(GPCRs)可激活SCCHN中的EGFR，导致细胞增殖和侵袭增加。这项建议将解决对SCCHN细胞生长和存活的影响，GPCR信号级联显示了双重机制：一种是EGFR独立的，另一种是与EGFR整合的。我们的初步结果表明，前列腺素E_2(PGE_2)及其受体和缓激肽(BK)及其受体这两个GPCR系统通过这种双重机制刺激SCCHN的增殖。这项建议的总体目标是证明通过PGE2和BK信号在头颈癌增殖中的机制和重要性，并开发这些GPCR途径的抑制剂与EGFR抑制剂联合治疗SCCHN的理论基础。长期目标是设计一项将EGFR抑制剂与PGE2或BK抑制剂相结合的临床试验，用于头颈癌患者。

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the head and neck (SCCHN) is known to develop through complex genetic and epigenetic alterations in genes that control cell proliferation, cell cycle, and cell survival. One set of genes that shows frequently altered expression are genes for growth factors and their receptors, including Epidermal Growth Factor Receptor (EGFR). G-protein- coupled receptors (GPCRs) have been shown to activate the EGFR in SCCHN, resulting in increased proliferation and invasion. This proposal will address the effect on SCCHN cell growth and survival of GPCR signaling cascades that show a dual mechanism: one that is EGFR-independent, as well as one that is integrated with the EGFR. Our preliminary results suggest that two GPCR systems, prostaglandin E2 (PGE2) and its receptors, and bradykinin (BK) and its receptors, stimulate SCCHN proliferation by this dual mechanism. The overall goal of this proposal is to demonstrate the mechanism and importance of signaling through PGE2 and BK in head and neck cancer proliferation, and develop a rationale for combining inhibitors of these GPCR pathways with EGFR inhibitors for the treatment of SCCHN. The long-term goal is to design a clinical trial combining EGFR inhibitors with inhibitors of PGE2 or BK for head and neck cancer patients.