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

磷酸肌醇-3-激酶信号传导和 PIK3CA：头部关键的有丝分裂驱动因素

• 批准号: 9064089
• 负责人: Matthew Louis Hedberg
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064089
• 关键词: Accounting; Affect; Agar; Alcohol consumption; Biological Assay; Biology; Cancerous; Cell Line; Cells; Clinical; Combined Modality Therapy; Complement; Coupled; Data Set; Death Rate; Development; Engineering; Epidemic; Evaluation; Event; Future; Genes; Genetic; Genetic Heterogeneity; Goals; Head; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Implant; In Vitro; Incidence; Infection; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Matrigel Invasion Assay; Mediating; Mission; Modeling; Mucous Membrane; Mus; Mutate; Mutation; Mutation Spectra; Neoplasms; Oncogenic; Oropharyngeal Head and Neck Squamous Cell Carcinoma; PIK3CA gene; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Population; Pre-Clinical Model; Predictive Value; Protein Array; Protein Array Analysis; Resected; Risk Factors; Signal Pathway; Signal Transduction; Staging; Survival Rate; TP53 gene; Testing; The Cancer Genome Atlas; Tobacco use; Treatment Efficacy; Xenograft procedure; actionable mutation; addiction; cohort; drug efficacy; effective therapy; evidence base; exome sequencing; gain of function mutation; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; kinase inhibitor; mutant; mutational status; next generation sequencing; novel therapeutics; preclinical evaluation; predictive marker; prospective; research clinical testing; research study; screening; small molecule inhibitor; targeted treatment; tumor

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.

头颈部鳞状细胞癌（Head and Neck Squamous Cell Carcinoma，HNSCC）是一种上呼吸消化道粘膜的侵袭性恶性肿瘤，占头颈部肿瘤的90%以上。HNSCC是世界范围内第6大最常见的癌症，每年在美国有> 40，000例新发病例，在全球有> 500，000例新发病例。10年生存率约为50%。主要的HNSCC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HNSCC的遗传异质性，加上对促成这种肿瘤发病机制的关键驱动事件和信号通路的知识空白。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（PI 3 K）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%的肿瘤在该途径中存在突变。已知PI 3 K的突变，特别是该途径中最常见的突变基因PIK 3CA中的突变导致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筛查平台来鉴定致癌表型，我们正在定义哪些PIK 3CA突变可以驱动HNSCC中的癌症。将采用反相蛋白阵列（RPPA）来表征这些突变改变的细胞信号传导途径，以在携带PIK 3CA突变和/或其他PI 3 K改变（例如PTEN缺失）的HNSCC的体外和体内模型中产生癌性表型。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的改变将增加这些药物的疗效。我们还将使用RPPA来分析这些药物改变这些癌症中细胞信号通路的方式。获得和比较这些配对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废除的信号通路，为联合治疗提供基于证据的靶点。最后，HPV（+）HNSCC的流行正在出现，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。我们将进行一项前瞻性测序项目，以确定现代临床HPV（+）HNSCC人群中PIK 3CA和其他癌症相关基因的突变状态，并启动实验以研究这种相关性的机制。这些研究的最终目标是根据NCI的使命声明，为HNSCC的下一代靶向治疗提供信息并改善其应用。

项目成果

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.

鼻咽癌的外显子组和基因组测序鉴定了NF-κB途径激活突变。

• DOI: 10.1038/ncomms14121
• 发表时间: 2017-01-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Li YY;Chung GT;Lui VW;To KF;Ma BB;Chow C;Woo JK;Yip KY;Seo J;Hui EP;Mak MK;Rusan M;Chau NG;Or YY;Law MH;Law PP;Liu ZW;Ngan HL;Hau PM;Verhoeft KR;Poon PH;Yoo SK;Shin JY;Lee SD;Lun SW;Jia L;Chan AW;Chan JY;Lai PB;Fung CY;Hung ST;Wang L;Chang AM;Chiosea SI;Hedberg ML;Tsao SW;van Hasselt AC;Chan AT;Grandis JR;Hammerman PS;Lo KW
• 通讯作者: Lo KW