Phosphoinositol-3-Kinase Signaling and PIK3CA: Critical Mitogenic Drivers in Head

项目摘要 摘要头颈部鳞状细胞癌(HNSCC)是一种侵袭性上呼吸道恶性肿瘤。 粘膜，占发生在头颈部的癌症的90%。HNSCC是第六种最常见的 按全球癌症发病率计算，美国每年新增4万例癌症病例，全球每年新增50万例。这个 10年生存率约为50%。HNSCC的主要危险因素包括吸烟和饮酒，以及感染 人类乳头瘤病毒(HPV)16.迄今为止治疗效果有限可能是由于基因 HNSCC的异质性，加上关于关键驱动事件和信号的知识差距 在这种肿瘤的发病机制中起作用的通路。我们和其他人最近阐明了 412例HNSCC肿瘤全外显子组测序分析我们的初步结果 证明磷酸肌醇-3-激酶(PI3K)途径是最常见的突变致癌基因 在HNSCC中，在迄今为止最大的队列中，~41%的肿瘤存在该途径的突变。基因突变 PI3K，特别是在该途径中最常见的突变基因PIK3CA中，已知与 HNSCC和其他恶性肿瘤中的癌症；尽管其机制尚不清楚。使用各种不同的 HNSCC筛查平台为了确定致癌表型，我们正在定义哪些PIK3CA突变可以 在HNSCC引发癌症。将使用反相蛋白质阵列(RPPA)来表征细胞 这些突变在体外和体内改变产生癌变表型的信号通路 HNSCC模型含有PIK3CA突变和/或其他PI3K改变，如PTEN缺失。 此外，我们将在这些模型中测试靶向PI3K抑制剂，因为我们预计PI3K的改变将 提高这些药物的疗效。我们还将使用RPPA来分析这些药物改变细胞的方式 这些癌症中的信号通路。获取和比较这些配对的数据集将使我能够识别 由致癌的PIK3CA突变改变的信号通路，并决定 被靶向抑制剂废除，为联合治疗提供循证靶点。最后，一场传染病的流行 HPV(+)HNSCC正在出现，1988至2004年间发病率增加了225%。回顾 测序研究表明，PIK3CA突变在HPV(+)HNSCC中尤其丰富。我们将进行一项 用于确定PIK3CA和其他癌症相关基因突变状态的前瞻性测序计划 在现代临床HPV(+)HNSCC人群中，并启动实验以探讨其机制 这种关联背后的原因是。这些研究的最终目标是提供信息并改进对 根据NCI的使命声明，针对HNSCC的下一代疗法。

Project Summary Head and neck squamous cell carcinoma (HNSCC) is an invasive malignancy of the upper aerodigestive tract mucosa, accounting for >90% of cancers that arise in the head and neck. HNSCC is the 6th most common cancer by incidence worldwide, with >40,000 new cases in the US, and >500,000 worldwide, each year. The 10 year survival rate is ~50%. Major HNSCC risk factors include tobacco and alcohol use, and infection with Human Papillomavirus (HPV) 16. The limited efficacy of therapies to date is likely due to the genetic heterogeneity of HNSCC, coupled with gaps in knowledge regarding the key driver events and signaling pathways that contribute to the pathogenesis of this neoplasm. We and others have recently elucidated the mutational profile of 412 HNSCC tumors through whole exome sequencing. Our preliminary results demonstrate that the Phosphoinositol-3-Kinase (PI3K) pathway is the most commonly mutated oncogenic pathway in HNSCC, ~41% of tumors in the largest cohort to date have mutations in this pathway. Mutations in PI3K, especially in the most commonly mutated gene in this pathway, PIK3CA, are known to contribute to cancer in HNSCC and other malignancies; though the mechanisms are poorly elucidated. Using a variety of HNSCC screening platforms to identify oncogenic phenotypes, we are defining which PIK3CA mutations can drive cancer in HNSCC. Reverse Phase Protein Arrays (RPPA) will be employed to characterize the cell signaling pathways that these mutations alter to generate cancerous phenotypes in both in vitro and in vivo models of HNSCC harboring PIK3CA mutations, and/or other PI3K alterations such as PTEN loss. Furthermore, we will test targeted PI3K inhibitors in these models, as we anticipate that PI3K alterations will increase the efficacy of these drugs. We will also use RPPA to analyze the ways in which these drugs alter cell signaling pathways in these cancers. Obtaining and comparing these paired datasets will allow me to identify the signaling pathways altered by oncogenic PIK3CA mutations, and determine the signaling pathways that are abrogated by targeted inhibitors, offering evidence-based targets for combined therapy. Finally, an epidemic of HPV(+)HNSCC is emerging, with incidence rates increasing 225% between 1988 and 2004. Retrospective sequencing studies suggest PIK3CA mutations are especially enriched in HPV(+)HNSCC. We will conduct a prospective sequencing project to define the mutational status of PIK3CA and other cancer associated genes in modern clinical HPV(+)HNSCC populations, and initiate experiments to investigate the mechanisms underlying this correlation. The ultimate goal of these studies is to inform and improve the application of targeted next generation therapeutics in HNSCC, in accordance with the mission statement of the NCI.