GPCR Signaling in SCCHN: Integration with EGFR

SCCHN 中的 GPCR 信号转导：与 EGFR 整合

• 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
• 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

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.

摘要 头颈部鳞状细胞癌(HNSCC)通常是致命的和可预测的生物标记物 缺乏治疗。2006年，FDA批准EGFR靶向治疗HNSCC。EGFR信号通过以下方式激活 G蛋白偶联受体(GPCR)直接刺激和反式激活。我们之前发现了gpr- 诱导EGFR上游和下游的磷脂酰肌醇-3-激酶(PI3K)激活。共同瞄准 PI3K联合EGFR抑制与HNSCC抗肿瘤作用增强相关 临床前模型。我们最近完成了一项随机、安慰剂对照、机会之窗的临床试验 使用厄洛替尼联合GPCR抑制剂/非甾体抗炎药舒林酸显著降低肿瘤的试验 扩散。阿司匹林和舒林酸一样，可以抑制环氧合酶(COX)和gpr信号转导。一项关于结肠的最新研究 癌症报道，在肿瘤携带PIK3CA突变的患者中使用阿司匹林与 与含有野生型(WT)PIK3CA的肿瘤患者相比，患者的生存期显著延长。我们有 现在确定了HNSCC的突变情况，并在近25%的肿瘤中发现了PIK3CA基因改变。 初步结果表明，PIK3CA突变增强了对非甾体抗炎药治疗的敏感性。因为非甾体抗炎药是 容忍度良好，这为实施潜在有效的方法提供了一个直接的机会 PIK3CA突变体HNSCC。我们开发了新的HNSCC模型来识别这一致癌“驱动”突变 癌症。此外，我们还可以评估PIK3CA在人HNSCC肿瘤中的突变和扩增 作为异位肿瘤移植物在小鼠和HNSCC队列中使用，已知使用非类固醇抗炎药。这个项目将阐明 PIK3CA改变在单独或与EGFR拮抗剂联合应用中对非类固醇抗炎药敏感性的调节作用 在HNSCC。