GRPR Signaling in SCCHN: Integration with EGFR

SCCHN 中的 GRPR 信号转导：与 EGFR 整合

• 批准号: 7035250
• 负责人: Jennifer Rubin Grandis
• 金额: $ 39.71万
• 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: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035250
• 关键词: antisense nucleic acid; apoptosis; autocrine; biological signal transduction; carcinogenesis; cell migration; cell proliferation; combination chemotherapy; epidermal growth factor; gastrin releasing peptide; growth factor receptors; head /neck neoplasm; laboratory mouse; metalloendopeptidases; molecular oncology; monoclonal antibody; neuropeptide receptor; neutralizing antibody; nonhuman therapy evaluation; oligonucleotides; protein tyrosine kinase; receptor expression; squamous cell carcinoma; xenotransplantation

DESCRIPTION (provided by applicant): An autocrine pathway involving gastrin releasing peptide receptor (GRPR) and its ligand, gastrin-releasing peptide (GRP) has been implicated in carcinogenesis. Clinical trials are underway in lung cancer patients to investigate the efficacy of therapies that specifically interfere with GRP/GRPR. We have extensive evidence implicating TGF-alpha/EGFR autocrine signaling in squamous cell carcinoma of the head and neck (SCCHN), where EGFR expression is associated with decreased survival. EGFR targeting strategies are actively under investigation in patients with SCCHN. G-protein-coupled receptors (GPCRs), like GRPR, have been shown to activate EGFR via several potential pathways. Furthermore, GRPR blockade has been associated with EGFR downmodulation. GRPR signaling has not been investigated in SCCHN. We previously reported that GRPR is upregulated early in SCCHN carcinogenesis, and that abrogation of GRP/GRPR results in SCCHN growth inhibition in vitro and in vivo. We recently reported that GRP stimulates EGFR phosphorylation and mitogenesis through an EGFR-dependent and MAPK-dependent pathway in SCCHN cells. Further evidence implicates cleavage of EGFR proligands (including TGF-alpha and Amphiregulin) and Src family kinases in this process. Therefore, we propose to test the hypothesis that a GRPR autocrine pathway contributes to SCCHN carcinogenesis, in part, via activation of EGFR mitogenic signaling. In aim 1 we propose to determine the molecular mechanism of EGFR activation by GRP in SCCHN by elucidating the role of EGFR ligand and the contribution of Src family kinases. In aim 2, we will investigate the role of EGFR signaling pathways in mediating the biologic effects induced by GRP by determining: a) the EGFR-dependent and EGFR-independent pathways induced by GRP; and b) the additive or synergistic effects of stimulating/inhibiting both EGFR/GRPR on growth and signaling pathways. Aim 3 will determine the mechanisms and anti-tumor efficacy of combined GRPR/EGFR targeting in SCCHN models in vitro and in vivo by elucidating: a) the consequences of GRP/GRPR blockade and EGFR targeting on SCCHN cells in vitro; b) the therapeutic potential of GRP/GRPR targeting in combination with EGFR blockade in SCCHN xenograft models; and c) the mechanism of combination therapy.

描述（由申请人提供）：涉及胃泌素释放肽受体（GRPR）及其配体胃泌素释放肽（GRP）的自分泌途径与癌发生有关。 正在进行肺癌患者的临床试验，以研究特异性干扰 GRP/GRPR 的疗法的疗效。我们有大量证据表明头颈鳞状细胞癌 (SCCHN) 中存在 TGF-α/EGFR 自分泌信号传导，其中 EGFR 表达与生存率降低相关。 EGFR 靶向策略正在 SCCHN 患者中积极研究。 G 蛋白偶联受体 (GPCR)，如 GRPR，已被证明可以通过多种潜在途径激活 EGFR。 此外，GRPR 阻断与 EGFR 下调有关。 SCCHN 中尚未研究 GRPR 信号传导。我们之前报道过，GRPR 在 SCCHN 癌变早期上调，并且消除 GRP/GRPR 会导致 SCCHN 体外和体内生长抑制。 我们最近报道，GRP 在 SCCHN 细胞中通过 EGFR 依赖性和 MAPK 依赖性途径刺激 EGFR 磷酸化和有丝分裂发生。 进一步的证据表明 EGFR 配体（包括 TGF-α 和双调蛋白）和 Src 家族激酶在此过程中发生裂解。 因此，我们建议检验 GRPR 自分泌途径部分通过激活 EGFR 有丝分裂信号传导导致 SCCHN 致癌的假设。在目标 1 中，我们建议通过阐明 EGFR 配体的作用和 Src 家族激酶的贡献来确定 SCCHN 中 GRP 激活 EGFR 的分子机制。 在目标 2 中，我们将通过确定以下因素来研究 EGFR 信号传导通路在介导 GRP 诱导的生物效应中的作用： a) GRP 诱导的 EGFR 依赖性和 EGFR 独立通路； b) 刺激/抑制 EGFR/GRPR 对生长和信号传导途径的累加或协同效应。目标 3 将通过阐明以下内容，在体外和体内 SCCHN 模型中确定联合 GRPR/EGFR 靶向的机制和抗肿瘤功效： a) GRP/GRPR 阻断和 EGFR 靶向体外 SCCHN 细胞的后果； b) GRP/GRPR 靶向联合 EGFR 阻断在 SCCHN 异种移植模型中的治疗潜力； c) 联合治疗的机制。