PI3K Pathway Mutations in Head and Neck Cancer

头颈癌中的 PI3K 通路突变

基本信息

批准号：
10398070
负责人：
Jennifer Rubin Grandis
金额：
$ 63.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398070
关键词：
Address Affinity Chromatography Biological Biological Markers CRISPR screen Cell Line Cells Chronic Clinical Cytotoxic Chemotherapy Data Dependence Drug resistance ERBB3 gene Enrollment Epidermal Growth Factor Receptor Funding Genetic Goals Growth HPV-negative head and neck cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Immune Immune checkpoint inhibitor Immunocompetent Individual Infection Investigation Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Modeling Mutate Mutation Oncogenes Oncoproteins Oropharyngeal Outcome PIK3CA gene Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Pre-Clinical Model Prognosis Proteins Radiation therapy Reporting Resistance Signal Pathway Signal Transduction Site Testing Therapeutic Tumor-infiltrating immune cells United States Food and Drug Administration anti-PD1 antibodies antitumor effect base cancer cell clinical practice clinical translation effective therapy food standard gain of function improved kinase inhibitor mouse model mutant mutational status patient derived xenograft model predictive marker protein protein interaction targeted agent therapeutic target tobacco exposure treatment strategy tumor

项目摘要

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.

头颈部鳞状细胞癌（HNSCC）是病态和致命的恶性肿瘤在增加对表征该癌症的遗传改变的理解中尚未确定预测性生物标志物来指导治疗。PIK3CA是最多的在两个人乳头瘤病毒（HPV）中通常改变了癌基 - 负（34％病例）和HPV阳性（占病例的56％）HNSCC。在当前的资金期间我们发现 PIK3CA突变或扩增是HNSCC和只有PIK3CA突变的HNSCC肿瘤的一部分对PI3K途径敏感抑制。进一步的研究表明，HPV癌蛋白调节抗毒素 PI3K抑制剂的作用。我们假设阐明了生物学的影响 PI3K抑制剂耐药性的单个PIK3CA改变和机制将指导改善肿瘤患者的临床结果的治疗策略包含激活PI3K信号传导的遗传改变。为了检验这一假设提案三个具体目标。特定目标1将阐明蛋白质相互作用组和每个突变体P110α的合成致死依赖性证明了“驱动” HNSCC 使用：a）HPV+和HPV-中的亲和力纯度质谱（AP-MS） HNSCC模型； b）遗传相互作用CRISPR筛选。在目标2中，我们将确定单独靶向PI3K并结合抑制的影响免疫能力和免疫缺陷的HNSCC临床前模型。 AIM 3将检查PI3K的生物标志物通过分析的成对生物测量和PDX的抑制剂耐药性 HNSCC患者参加了p110αPI3K抑制剂的大型运动窗口试验 BYL719。这些研究的成功完成有可能改变临床通过根据患者提供有效的患者治疗策略，在HNSCC中进行练习其肿瘤的特定PIK3CA突变状态。