PI3K Pathway Mutations in Head and Neck Cancer

头颈癌中的 PI3K 通路突变

• 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
• 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

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.

头颈部鳞状细胞癌是一种恶性肿瘤 对这种癌症的遗传变异的理解 PIK 3CA是迄今为止发现的最具预测性的生物标志物， 在人乳头瘤病毒（HPV）阴性（34%）的患者中， 例）和HPV阳性（56%的病例）HNSCC。在当前的融资期内，我们发现 PIK 3CA突变或扩增是HNSCC预后不良的生物标志物， 只有一部分PIK 3CA突变的HNSCC肿瘤对PI 3 K通路敏感， 抑制作用进一步的研究表明，HPV癌蛋白调节抗肿瘤细胞的增殖， PI 3 K抑制剂的作用。我们假设， 个体PIK 3CA改变和PI 3 K抑制剂抗性的机制将指导 改善HNSCC患者临床结局的治疗策略， 含有激活PI 3 K信号的基因改变。为了验证这一假设， 提出三个具体目标。具体目标1将阐明蛋白质相互作用组， 证明每种突变p110α的合成致死依赖性“驱动”HNSCC a）在HPV+和HPV-中的亲和纯化-质谱（AP-MS） HNSCC模型;和B）遗传相互作用CRISPR筛选。在目标2中， 确定单独靶向PI 3 K和与抑制PI 3 K结合的影响。 在免疫活性细胞和非免疫活性细胞中的单个突变p110α-相互作用蛋白 免疫缺陷型HNSCC临床前模型。目标3将检查PI 3 K的生物标志物 通过分析配对生物标本和PDX， 入组p110α PI 3 K抑制剂机会窗试验的HNSCC患者 BYL719.这些研究的成功完成有可能改变临床 根据HNSCC的临床实践，为患者提供有效的治疗策略 其肿瘤的特定PIK 3CA突变状态。