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）：一种涉及胃泌素释放肽受体（GRPR）及其配体的自分泌途径与癌变有关。 肺癌患者正在进行临床试验，以研究特别干扰GRP/GRPR的疗法的功效。我们有大量的证据，暗示了头颈鳞状细胞癌（SCCHN）中TGF-Alpha/EGFR自分泌信号传导，其中EGFR表达与生存率降低有关。 EGFR靶向策略正在积极研究SCCHN患者。 G蛋白偶联受体（GPCR）（例如GRPR）已被证明可以通过多种潜在途径激活EGFR。 此外，GRPR封锁与EGFR下调有关。 尚未在SCCHN中研究GRPR信号。我们先前报道说，GRPR在SCCHN癌发生早期被上调，并且废除GRP/GRPR会导致SCCHN生长抑制体外和体内。 我们最近报道，GRP通过SCCHN细胞中的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，在这一过程中，EGFR催生（包括TGF-Alpha和Amphiregulin）和SRC家族激酶的裂解。 因此，我们建议检验以下假设：GRPR自分泌途径有助于SCCHN致癌作用，部分原因是通过激活EGFR有丝分裂信号传导。在AIM 1中，我们建议通过阐明EGFR配体的作用和SRC家族激酶的作用来确定GRP在SCCHN中的EGFR激活的分子机制。 在AIM 2中，我们将通过确定：a）GRP引起的EGFR信号通路在介导GRP引起的生物学效应中的作用； b）刺激/抑制EGFR/GRPR对生长和信号通路的累加或协同作用。 AIM 3将通过阐明：a）在体外和体内确定grpr/eGFR靶向联合grpr/eGFR靶向的机制和抗肿瘤功效： b）在SCCHN异种移植模型中，GRP/GRPR靶向与EGFR阻滞结合的治疗潜力； c）联合疗法的机制。