GPCR Signaling in SCCHN: Integration with EGFR

SCCHN 中的 GPCR 信号转导：与 EGFR 整合

基本信息

批准号：
8606299
负责人：
Jennifer Rubin Grandis
金额：
$ 27.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606299
关键词：
Accounting Address Aspirin Binding Biological Markers Cell Line Clinical Clinical Treatment Clinical Trials Colon Carcinoma Colorectal Cancer Development Diagnosis Dinoprostone Disease Enzymes Epidemiologic Studies Epidermal Growth Factor Receptor Erlotinib FDA approved Family Funding G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Amplification Gene Mutation Growth Head and Neck Squamous Cell Carcinoma Head and neck structure Human Human Papillomavirus Ligands Malignant Epithelial Cell Malignant Neoplasms Mediating Modeling Molecular Mus Mutate Mutation Non-Steroidal Anti-Inflammatory Agents Oncogenic PDPK1 gene PIK3CA gene Pathway interactions Patients Phosphatidylinositols Phosphotransferases Placebo Control Pre-Clinical Model Prevention strategy Prostaglandin-Endoperoxide Synthase Proto-Oncogene Proteins c-akt Randomized Receptor Activation Receptor Inhibition Receptor Signaling Regulatory Pathway Reporting Role Secondary Prevention Signal Transduction Subgroup Sulindac Testing Therapeutic Transactivation autocrine cohort cyclooxygenase 2 inhibitor/antagonist mutant novel pre-clinical prevent public health relevance receptor expression response therapeutic target tumor

项目摘要

ABSTRACT Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide therapy are lacking. EGFR targeting was FDA-approved in 2006 for HNSCC. EGFR signaling is activated by direct stimulation and transactivation by G-protein-coupled receptors (GPCR). We previously identified GPCR- induced activation of phosphoinositide-3-kinase (PI3K) both upstream and downstream of EGFR. Co-targeting of PI3K in combination with EGFR inhibition was associated with enhanced antitumor effects in HNSCC preclinical models. We recently completed a randomized, placebo-controlled, window-of-opportunity clinical trial where treatment with erlotinib plus the GPCR inhibitor/NSAID sulindac significantly reduced tumor proliferation. Aspirin, like sulindac, inhibits cyclooxygenase (COX) and GPCR signaling. A recent study in colon cancer reported that aspirin use in patients whose tumors harbored PIK3CA mutations was associated with significantly longer survival compared with patients whose tumors contained wild-type (WT) PIK3CA. We have now determined the mutational profile of HNSCC and find PIK3CA genetic alterations in nearly 25% of tumors. Preliminary results indicate that PIK3CA mutation enhances sensitivity to NSAID treatment. As NSAIDs are well tolerated, this provides an immediate opportunity to implement potentially effective approaches for PIK3CA mutant HNSCC. We developed novel HNSCC models to identify oncogenic "driver" mutations in this cancer. In addition, we can assess PIK3CA mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice and in a HNSCC cohort with known NSAID use. This project will elucidate the role of PIK3CA alterations in mediating sensitivity to NSAIDs, alone or in combination with EGFR blockade in HNSCC.

抽象的头部和颈部鳞状细胞癌（HNSCC）经常是致命的和预测的生物标志物缺乏治疗。 EGFR靶向于2006年对HNSCC进行了FDA批准。 EGFR信号被激活 G蛋白偶联受体（GPCR）直接刺激和反式激活。我们以前确定了GPCR- EGFR的上游和下游诱导的磷酸肌醇3-激酶（PI3K）的激活。共同目标与EGFR抑制结合使用PI3K与HNSCC中的抗肿瘤作用增强有关临床前模型。我们最近完成了一个随机的，安慰剂对照的临床窗口用厄洛替尼加GPCR抑制剂/NSAID Sulindac的试验显着降低了肿瘤增殖。阿司匹林，例如苏琳克，抑制环氧酶（COX）和GPCR信号传导。结肠的最新研究癌症报告说，阿司匹林在肿瘤中含有PIK3CA突变的患者中使用与肿瘤含有野生型（WT）PIK3CA的患者相比，生存期明显更长。我们有现在，确定了HNSCC的突变特征，并在近25％的肿瘤中发现了PIK3CA遗传改变。初步结果表明，PIK3CA突变增强了对NSAID治疗的敏感性。如NSAID所示宽容良好，这为实施潜在有效的方法提供了立即的机会 PIK3CA突变体HNSCC。我们开发了新型的HNSCC模型，以识别其中的致癌“驱动器”突变癌症。此外，我们可以评估人类HNSCC肿瘤中的PIK3CA突变和扩增作为小鼠和HNSCC队列中具有已知NSAID使用的HETOPIC肿瘤的肿瘤。这个项目将阐明 PIK3CA改变在介导对NSAID的敏感性中的作用，单独或与EGFR封锁结合在HNSCC中。