GPCR Signaling in SCCHN: Integration with EGFR

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）通常是致命的，缺乏指导治疗的预测性生物标志物。EGFR靶向治疗于2006年被fda批准用于HNSCC。EGFR信号通过g蛋白偶联受体（GPCR）的直接刺激和反激活激活。我们之前在EGFR的上游和下游都发现了GPCR诱导的磷酸肌醇激酶（PI3K）的激活。在HNSCC临床前模型中，PI3K联合EGFR抑制与增强的抗肿瘤作用相关。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，厄洛替尼加GPCR抑制剂/非甾体抗炎药舒林酸治疗可显著降低肿瘤增殖。阿司匹林，像舒林酸，抑制环氧化酶（COX）和GPCR信号。最近的一项结肠癌研究报告称，与含有野生型（WT） PIK3CA的肿瘤患者相比，携带PIK3CA突变的肿瘤患者使用阿司匹林可显著延长生存期。我们现在已经确定了HNSCC的突变谱，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的敏感性。由于非甾体抗炎药耐受性良好，这为PIK3CA突变型HNSCC提供了一个立即实施潜在有效方法的机会。我们开发了新的HNSCC模型来识别这种癌症的致癌“驱动”突变。此外，我们可以评估在小鼠和已知使用非甾体抗炎药的HNSCC队列中作为异位肿瘤移植物生长的人类HNSCC肿瘤中的PIK3CA突变和扩增。该项目将阐明PIK3CA改变在HNSCC中单独或联合EGFR阻断介导非甾体抗炎药敏感性中的作用。

DESCRIPTION (provided by applicant): 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, inhibit 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.