GPCR Signaling in SCCHN: Integration with EGFR

摘要 头颈部鳞状细胞癌（HNSCC）通常是致命的和预测性的生物标志物， 缺乏治疗。EGFR靶向在2006年被FDA批准用于HNSCC。EGFR信号被激活， 通过G蛋白偶联受体（GPCR）直接刺激和反式激活。我们之前鉴定过气相聚合酶链式反应- 诱导EGFR上游和下游的磷酸肌醇-3-激酶（PI 3 K）活化。共同靶 PI 3 K联合EGFR抑制与HNSCC中增强的抗肿瘤作用相关 临床前模型。我们最近完成了一项随机、安慰剂对照、机会之窗的临床研究， 厄洛替尼联合GPCR抑制剂/NSAID舒林酸治疗显著减少肿瘤的试验 增殖阿司匹林与舒林酸一样，抑制环氧合酶（考克斯）和GPCR信号传导。最近一项关于结肠的研究 癌症报告称，在肿瘤携带PIK 3CA突变的患者中使用阿司匹林与 与肿瘤含有野生型（WT）PIK 3CA的患者相比，PIK 3CA具有显著更长的存活期。我们有 现在确定了HNSCC的突变谱，并在近25%的肿瘤中发现了PIK 3CA基因改变。 初步结果表明，PIK 3CA突变增强了对NSAID治疗的敏感性。因为NSAID是 这是一个很好的容忍，这提供了一个直接的机会，实施潜在的有效方法， PIK 3CA突变体HNSCC。我们开发了新的HNSCC模型，以识别这种肿瘤中的致癌“驱动”突变。 癌此外，我们可以评估待生长的人HNSCC肿瘤中的PIK 3CA突变和扩增。 作为小鼠和已知使用NSAID的HNSCC队列中的异位肿瘤移植物。该项目将阐明 PIK 3CA改变在介导NSAID敏感性中的作用，单独或与EGFR阻断剂联合使用 在HNSCC。

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.