Targeting Alterations of the NOTCH1 Pathway in Head & Neck Squamous Cell Carcinoma (HNSCC)

针对头部 NOTCH1 通路的改变

• 批准号: 10020366
• 负责人: MITCHELL J. FREDERICK
• 金额: $ 65.08万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020366
• 关键词: Address; Aftercare; Cancer Etiology; Cell Cycle Arrest; Cell Death; Cell Line; Cessation of life; Cleaved cell; Clinical; Clinical Trials; Combined Modality Therapy; DNA Sequence Alteration; Data; Dependence; Development; Disease; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Esophagus; Exhibits; Exposure to; FRAP1 gene; Failure; Gene Mutation; Genes; Genomics; Growth; Head and Neck Squamous Cell Carcinoma; In Vitro; Incidence; Individual; Link; Lung; Malignant Neoplasms; Mediating; Molecular; Mutate; Mutation; NOTCH1 gene; PI3K/AKT; PIK3CA gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phosphatidylinositols; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Recurrence; Regulation; Reporting; Research; Resistance; Signal Pathway; Signal Transduction; Skin; Squamous cell carcinoma; Survival Rate; Testing; The Cancer Genome Atlas; Therapeutic; Tumor Suppressor Proteins; Work; aurora B kinase; biomarker-driven; cancer type; care outcomes; clinical care; clinically relevant; drug-sensitive; experience; genomic data; improved; in vivo; inhibitor/antagonist; insight; loss of function mutation; mTOR Inhibitor; molecular targeted therapies; mutant; neoplastic cell; new therapeutic target; personalized medicine; phosphoinositide-dependent kinase 1; potential biomarker; pre-clinical; preclinical study; prevent; prospective; response; targeted treatment; tumor

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the seventh leading cause of cancer-related deaths worldwide, and thus far the genomic alterations identified in this disease have not had an impact on clinical care. Our group was among the first to report frequent inactivating mutations of NOTCH1 in HNSCC. More recently, the incidence of NOTCH1 mutations was found to be roughly 20% among over 500 patient HNSCC tumors sequenced as part of The Cancer Genome Atlas (TCGA) project, placing NOTCH1 among the top five most frequently mutated genes in this cancer type. HNSCC cell lines harboring NOTCH1 mutations are significantly more sensitive to six different drugs targeting the PI3K/mTOR pathway than HNSCC cell lines with wild-type (wt) NOTCH1. Unlike HNSCC tumors with PIK3CA mutations, which exhibited only growth arrest after treatment with PI3K/mTOR inhibitors, cell lines harboring NOTCH1 mutation also underwent cell death. Proteomic profiling of drug-sensitive HNSCC cell lines harboring NOTCH1 mutations and drug-resistant HNSCC lines with wt NOTCH1 before and after drug treatment revealed no differences in the modulation of many drug targets directly downstream of PI3K, including AKT. However, NOTCH1 mutants experienced greater drug-induced decreases in total expression of 3-phosphoinositide dependent kinase 1 (PDK1) and Aurora kinase B. Collectively, these data led to the hypothesis that HNSCC tumors with NOTCH1 mutations are highly sensitive to PI3K inhibitors because the PI3K signaling pathway is uniquely tied to regulation of total PDK1 protein levels, impacting both phosphatidylinositol-dependent and -independent PDK1 function in this genomic subtype. Therefore, drugs targeting PI3K/mTOR should be effective for treating HNSCC patients with NOTCH1-mutant tumors. We will address these hypotheses with a clinical trial (Aim 1) and conduct in vitro mechanistic studies (Aim 2) and preclinical studies to identify ways to enhance killing of HNSCC tumors harboring NOTCH1 mutations through combination therapy (Aim 3). The proposed research will have a positive impact because it will be the first to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC to any class of drugs and may inform the development of the first biomarker-driven targeted therapy for HNSCC. Additionally, we may define a previously unknown mechanism of PDK1 regulation and identify clinically relevant targets that enhance the efficacy and durability of PI3K inhibition in NOTCH1-mutant HNSCC. Because NOTCH1 loss-of-function mutations are common in other squamous cell carcinomas, including those of the skin, esophagus, and lung, these findings will likely have implications beyond HNSCC.

项目概要 头颈鳞状细胞癌 (HNSCC) 是癌症相关死亡的第七大原因 在世界范围内，迄今为止在这种疾病中发现的基因组改变尚未对临床产生影响 关心。我们的团队是最早报告 HNSCC 中 NOTCH1 频繁失活突变的团队之一。更多的 最近，在超过500名HNSCC患者中发现NOTCH1突变的发生率约为20% 作为癌症基因组图谱 (TCGA) 项目一部分进行测序的肿瘤，NOTCH1 跻身前五名 这种癌症类型中最常见的突变基因。携带 NOTCH1 突变的 HNSCC 细胞系是 与 HNSCC 细胞系相比，对针对 PI3K/mTOR 通路的六种不同药物显着更敏感 野生型（wt）NOTCH1。与仅表现出生长停滞的具有 PIK3CA 突变的 HNSCC 肿瘤不同 用 PI3K/mTOR 抑制剂治疗后，携带 NOTCH1 突变的细胞系也经历了细胞死亡。 含有 NOTCH1 突变和耐药的药物敏感 HNSCC 细胞系的蛋白质组学分析 具有 wt NOTCH1 的 HNSCC 系在药物治疗前后显示在调节方面没有差异 许多药物直接作用于 PI3K 下游，包括 AKT。然而，NOTCH1突变体经历了 药物诱导的 3-磷酸肌醇依赖性激酶 1 (PDK1) 总表达降低幅度更大， 极光激酶 B。总的来说，这些数据得出这样的假设：具有 NOTCH1 突变的 HNSCC 肿瘤 对 PI3K 抑制剂高度敏感，因为 PI3K 信号通路与总调节相关 PDK1 蛋白水平，影响磷脂酰肌醇依赖性和非依赖性 PDK1 功能 基因组亚型。因此，针对 PI3K/mTOR 的药物对于治疗 HNSCC 患者应该是有效的。 NOTCH1-突变肿瘤。我们将通过临床试验（目标 1）来解决这些假设，并在体外进行 机制研究（目标 2）和临床前研究，以确定增强 HNSCC 肿瘤杀灭的方法 通过联合治疗携带 NOTCH1 突变（目标 3）。拟议的研究将有一个 积极影响，因为它将是第一个确定 NOTCH1 突变型 HNSCC 的治疗脆弱性的研究 任何类别的药物，并可能为第一个生物标志物驱动的 HNSCC 靶向治疗的开发提供信息。 此外，我们可以定义一种以前未知的 PDK1 调节机制，并在临床上进行鉴定 增强 PI3K 抑制在 NOTCH1 突变型 HNSCC 中的功效和持久性的相关靶标。 因为 NOTCH1 功能丧失突变在其他鳞状细胞癌中很常见，包括那些 皮肤、食道和肺部的疾病，这些发现可能会影响 HNSCC 以外的领域。