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

项目摘要 头颈部鳞状细胞癌是上呼吸消化道的一种侵袭性恶性肿瘤 在头颈部发生的癌症中，粘膜癌占>90%。HNSCC是第六常见的 癌症在全球范围内的发病率，美国每年有> 40，000例新发病例，全球每年有> 500，000例新发病例。的 10年生存率约为50%。HNSCC的主要风险因素包括吸烟和饮酒以及感染 人乳头瘤病毒（HPV）16.迄今为止，治疗的有限疗效可能是由于遗传因素， HNSCC的异质性，加上关于关键驱动事件和信号传导的知识空白 导致这种肿瘤发病的途径。我们和其他人最近阐明了 412例HNSCC肿瘤通过全外显子组测序的突变谱。我们的初步结果 证明磷酸肌醇-3-激酶（PI 3 K）途径是最常见的突变致癌基因， 在HNSCC中，约41%的肿瘤在该途径中存在突变。突变 已知PI 3 K，特别是在该途径中最常见的突变基因PIK 3CA中， HNSCC和其他恶性肿瘤中的癌症;尽管机制尚不清楚。使用各种 HNSCC筛选平台，以确定致癌表型，我们正在定义哪些PIK 3CA突变可以 在HNSCC中引发癌症。将采用反相蛋白质阵列（RPPA）表征细胞 这些突变改变的信号通路在体外和体内产生癌性表型 携带PIK 3CA突变和/或其他PI 3 K改变如PTEN缺失的HNSCC模型。 此外，我们将在这些模型中测试靶向PI 3 K抑制剂，因为我们预计PI 3 K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。获取并比较这些成对的数据集将使我能够识别 致癌PIK 3CA突变改变的信号通路，并确定 被靶向抑制剂消除，为联合治疗提供循证靶点。最后， HPV（+）HNSCC正在出现，1988年至2004年期间发病率增加了225%。回顾性 测序研究表明PIK 3CA突变在HPV（+）HNSCC中尤其富集。我们将进行 前瞻性测序项目，以确定PIK 3CA和其他癌症相关基因的突变状态 在现代临床HPV（+）HNSCC人群中，并启动实验以研究其机制 这一关联的基础。这些研究的最终目标是为信息和改善应用 根据NCI的使命声明，HNSCC的下一代靶向治疗。

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.