TARGETING EGFR AND GPCR SIGNALING IN SCCHN

SCCHN 中靶向 EGFR 和 GPCR 信号传导

• 批准号: 6990399
• 负责人: Jill M Siegfried
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990399
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; bradykinin; carcinogenesis inhibitor; cell growth regulation; cell proliferation; cell surface receptors; enzyme linked immunosorbent assay; epidermal growth factor; gene targeting; growth factor receptors; head /neck neoplasm; human tissue; neoplasm /cancer therapy; prostaglandin E; protein signal sequence; squamous cell carcinoma; tissue /cell culture; western blottings

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.

描述（由申请人提供）：已知头颈鳞状细胞癌 (SCCHN) 是通过控制细胞的基因中复杂的遗传和表观遗传改变而发生的 增殖、细胞周期和细胞存活。一组表现出频繁改变的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 (GPCR) 已被证明可以激活 SCCHN 中的 EGFR，从而导致增殖和侵袭增加。该提案将解决 GPCR 信号级联对 SCCHN 细胞生长和存活的影响，该级联显示出双重机制：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 E2 (PGE2) 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 增殖。该提案的总体目标是证明通过 PGE2 和 BK 信号传导在头颈癌增殖中的机制和重要性，并为将这些 GPCR 通路抑制剂与 EGFR 抑制剂联合治疗 SCCHN 提供依据。长期目标是针对头颈癌患者设计一项将 EGFR 抑制剂与 PGE2 或 BK 抑制剂相结合的临床试验。