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靶向在2006年被FDA批准用于HNSCC。EGFR信号传导通过直接刺激和G蛋白偶联受体（GPCR）的反式激活来激活。我们先前鉴定了EGFR上游和下游的磷酸肌醇-3-激酶（PI 3 K）的GPCR诱导的活化。在HNSCC临床前模型中，PI 3 K的共靶向与EGFR抑制的组合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、机会之窗临床试验，其中厄洛替尼联合GPCR抑制剂/NSAID舒林酸治疗显著降低了肿瘤增殖。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。最近的一项结肠癌研究报告称，与肿瘤含有野生型（WT）PIK 3CA的患者相比，在肿瘤含有PIK 3CA突变的患者中使用阿司匹林与显著延长的生存期相关。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。由于NSAID耐受性良好，这为实施PIK 3CA突变型HNSCC的潜在有效方法提供了直接机会。我们开发了新的HNSCC模型来鉴定这种癌症中的致癌“驱动”突变。此外，我们可以评估人HNSCC肿瘤中的PIK 3CA突变和扩增，所述人HNSCC肿瘤在小鼠中和在具有已知NSAID使用的HNSCC群组中作为异位肿瘤移植物生长。该项目将阐明PIK 3CA改变在HNSCC中介导对NSAID敏感性的作用，单独或与EGFR阻断剂联合使用。

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.