PI3K Pathway Mutations in Head and Neck Cancer

头颈部鳞状细胞癌(HNSCC)是一种致死性和致命性的恶性肿瘤。 在那里，人们对这种癌症的基因改变的了解越来越多 尚未确定预测生物标记物来指导治疗。PIK3CA是最 人类乳头瘤病毒(HPV)阴性的常见癌基因改变(34% 5例)和HPV阳性(56%)HNSCC。在当前的资助期内，我们发现 PIK3CA突变或扩增是HNSCC预后不良的生物标志物 只有部分PIK3CA突变的HNSCC肿瘤对PI3K通路敏感 抑制力。进一步的研究表明，HPV癌蛋白调节抗肿瘤作用 PI3K抑制剂的作用。我们假设，对生物影响的阐明 PIK3CA的个体变化和PI3K抑制剂耐药机制将指导 改善HNSCC患者临床预后的治疗策略 含有激活PI3K信号的基因改变。为了检验这一假设，我们 提出三个具体目标。特异性目标1将阐明蛋白质相互作用组和 每个突变型p110α的合成致死依赖关系被证明是“驱动”人类非小细胞肺癌的 存活使用：a)亲和纯化-质谱法(AP-MS)检测HPV+和HPV- HNSCC模型；以及b)遗传互作CRISPR筛选。在《目标2》中我们将 确定单独靶向PI3K以及联合抑制PI3K的影响 单个突变型p110α−相互作用蛋白在免疫活性和 免疫缺陷型HNSCC临床前模型。AIM 3将检测PI3K的生物标记物 通过分析成对的生物菌种和PDX来分析从 接受p110αPI3K抑制剂机会窗试验的非小细胞肺癌患者 BYL719。这些研究的成功完成有可能改变临床 在HNSCC中的实践，为患者提供基于 其肿瘤特异性PIK3CA突变状态。

Head and neck squamous cell carcinoma (HNSCC) is a morbid and lethal malignancy where increased understanding of the genetic alterations that characterize this cancer has yet to identify predictive biomarkers to guide therapy.PIK3CA is the most commonly altered oncogene in both human papillomavirus (HPV)- negative (34% of cases) and HPV-positive (56% of cases) HNSCC. In the current funding period we found that PIK3CA mutation or amplification is a biomarker of poor prognosis in HNSCC and that only a subset of PIK3CA- mutated HNSCC tumors are sensitive to PI3K pathway inhibition. Further investigation suggested that HPV oncoproteins regulate the antitumor effects of PI3K inhibitors. We hypothesize that elucidation of the biologic impact of individual PIK3CA alterations and mechanisms of PI3K inhibitor resistance will guide therapeutic strategies to improve clinical outcomes for HNSCC patients whose tumors contain genetic alterations that activate PI3K signaling. To test this hypothesis we propose three Specific Aims. Specific Aim 1 will elucidate the protein interactome and synthetic lethal dependencies for each mutant p110α demonstrated to “drive” HNSCC survival using: a) affinity purification- mass spectrometry (AP-MS) in HPV+ and HPV- HNSCC models; and b) genetic interaction CRISPR screening. In Aim 2 we will determine the impact of targeting PI3K alone and in combination with inhibition of individual mutant p110α−interacting proteins in both immunocompetent and immunodeficient HNSCC preclinical models. Aim 3 will examine biomarkers of PI3K inhibitor resistance by analyzing paired biospecimens and PDXs developed from HNSCC patients enrolled on a window-of-opportunity trial of the p110α PI3K inhibitor BYL719. Successful completion of these studies has the potential to change clinical practice in HNSCC by providing effective treatment strategies for patients based on the specific PIK3CA mutational status of their tumor.