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

项目概述头颈部鳞状细胞癌（Head and neck squamous cell carcinoma， HNSCC）是一种发生在上呼吸道消化道粘膜的侵袭性恶性肿瘤，约占头颈部肿瘤的90%。HNSCC是全球发病率第6高的癌症，在美国每年有40万新病例，在全球每年有50万新病例。10年生存率约为50%。主要的HNSCC危险因素包括吸烟和饮酒，以及感染人乳头瘤病毒（HPV）。迄今为止，治疗的有限疗效可能是由于HNSCC的遗传异质性，以及对导致这种肿瘤发病机制的关键驱动事件和信号通路的知识差距。我们和其他人最近通过全外显子组测序阐明了412例HNSCC肿瘤的突变谱。我们的初步结果表明，磷酸肌醇-3激酶（PI3K）途径是HNSCC中最常见的突变致癌途径，迄今为止最大队列中约41%的肿瘤在该途径中发生突变。PI3K的突变，特别是该通路中最常见的突变基因PIK3CA，已知会导致HNSCC和其他恶性肿瘤的癌症；尽管其机制尚不清楚。使用各种HNSCC筛选平台来确定致癌表型，我们正在确定哪些PIK3CA突变可以驱动HNSCC中的癌症。逆相蛋白阵列（RPPA）将用于表征这些突变在体外和体内HNSCC模型中产生癌变表型的细胞信号通路，这些突变包含PIK3CA突变和/或其他PI3K改变，如PTEN丢失。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的改变将增加这些药物的功效。我们还将使用RPPA来分析这些药物改变这些癌症细胞信号通路的方式。获得并比较这些配对数据集将使我能够识别由致癌PIK3CA突变改变的信号通路，并确定被靶向抑制剂取消的信号通路，为联合治疗提供循证靶点。最后，HPV(+)HNSCC的流行正在出现，1988年至2004年间发病率增加了225%。回顾性测序研究表明，PIK3CA突变在HPV(+)HNSCC中尤其丰富。我们将开展一项前瞻性测序项目，以确定现代临床HPV(+)HNSCC人群中PIK3CA和其他癌症相关基因的突变状态，并启动实验来研究这种相关性的机制。这些研究的最终目标是根据NCI的使命宣言，为下一代靶向治疗方法在HNSCC中的应用提供信息和改进。

DESCRIPTION (provided by applicant): 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.