Sphingosine-1-phosphate receptor subtype 3 in oncogenic K-Ras mutant-driven lung adenocarcinoma

K-Ras 突变驱动的肺腺癌中的 1-磷酸鞘氨醇受体亚型 3

• 批准号: 9317962
• 负责人: MENQ-JER LEE
• 金额: $ 18万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317962
• 关键词: Adenocarcinoma; Agar; Animal Cancer Model; Animals; Binding; Biochemical; CCL2 gene; Cancer Etiology; Cells; Cessation of life; Clinical; Data; Data Set; Development; Dominant-Negative Mutation; Dose; Ectopic Expression; Enterobacteria phage P1 Cre recombinase; Family; Future; G-Protein-Coupled Receptors; Genetically Engineered Mouse; Goals; Growth; Health; Human; Hyperplasia; In Vitro; Infiltration; Inflammation Mediators; Inflammatory; Injectable; Injection of therapeutic agent; Intervention; KRAS2 gene; Knowledge; Ligands; Lipids; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Methods; Mouse Strains; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Prognostic Marker; Proteins; Recruitment Activity; Refractory; Research; Research Design; Role; Serum; Signal Pathway; Signaling Molecule; Sphingosine-1-Phosphate Receptor; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Tumorigenicity; adenoma; chemokine; chemotherapy; cyclooxygenase 1; cyclooxygenase 2; data mining; effective intervention; effective therapy; extracellular; fight against; in vivo; inhibitor/antagonist; knock-down; lipid mediator; lung Carcinoma; lung development; macrophage; mouse model; mutant; mutational status; new therapeutic target; novel therapeutic intervention; particle; pre-clinical; ras Proteins; receptor; sphingosine 1-phosphate; targeted agent; therapeutic target; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

Objectives: K-Ras is a normal cellular protein. Oncogenic K-Ras mutation, leading to the exacerbated activation of K-Ras protein, causes tumor initiation and progression. K-Ras mutation is found in more than 25% of human non-small cell lung carcinomas (NSCLC). However, lung cancers caused by K-Ras mutation are generally refractory to chemotherapy as well as targeted agents. Moreover, the identification of drugs to therapeutically inhibit K-Ras has been unsuccessful, suggesting that other approaches are required. Sphingosine-1-phosphate (S1P) is an important lipid mediator present in our body. Levels of S1P receptor subtype 3 (S1PR3, a receptor which binds S1P and mediates S1P functions) are increased in lung carcinomas. S1PR3 regulates various tumorigenic functions which are critical for the progression of human lung adenocarcinoma (LADC). Inhibition of S1PR3 profoundly diminishes lung carcinoma growth in animals. Furthermore, oncogenic K-Ras mutant stimulates S1PR3 expression in vitro and in vivo. Collectively, the objectives of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC, and to investigate whether S1PR3 inhibition provides an effective therapy for K-Ras mutant-driven human LADC. Hypothesis, Specific aims, and Study designs: The hypothesis of this proposal is “Exacerbated S1PR3 activity contributes to oncogenic K-Ras mutant-driven LADC progression, at least in part, by promoting macrophage infiltration to LADC. S1PR3 represents a potential therapeutic target for the treatment of K-Ras mutant-driven LADC.” Two aims are proposed to test this hypothesis. Aim 1. A genetically engineered mouse strain, mice expressing mutated K-Ras protein and lacking S1PR3, will be utilized to determine the critical role of S1PR3 in K-Ras mutant-driven LADC. In addition, the role of S1PR3 in recruiting inflammatory macrophages to LADC will be investigated. Aim 2. TY-52156, a highly selective S1PR3 antagonist, will be used to demonstrate the proof-of-concept that S1PR3 inhibition is an effective intervention for oncogenic K-Ras mutant-driven LADC. Health relatedness of the project: Lung cancer remains the leading cause of cancer-related deaths. The main goal of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC progression. The successful completion of this application is expected to provide multiple intervention points for the fight against oncogenic K-Ras mutant-driven LADC in the future.

目的：K-Ras 是一种正常的细胞蛋白。致癌 K-Ras 突变，导致病情恶化 K-Ras 蛋白的激活导致肿瘤的发生和进展。超过 25% 的患者发现 K-Ras 突变 人类非小细胞肺癌（NSCLC）。然而，由 K-Ras 突变引起的肺癌 通常对化疗和靶向药物耐药。此外，药物鉴定 治疗性抑制 K-Ras 尚未成功，这表明需要其他方法。 1-磷酸鞘氨醇 (S1P) 是我们体内存在的重要脂质介质。 S1P受体水平 亚型 3（S1PR3，一种结合 S1P 并介导 S1P 功能的受体）在肺癌中增加。 S1PR3 调节各种致瘤功能，这对人肺的进展至关重要 腺癌（LADC）。抑制 S1PR3 可显着减少动物肺癌的生长。 此外，致癌的 K-Ras 突变体在体外和体内刺激 S1PR3 表达。总的来说， 本申请的目的是表征 S1PR3 在 K-Ras 突变驱动的 LADC 中的关键作用，并 研究 S1PR3 抑制是否为 K-Ras 突变驱动的人类 LADC 提供有效的治疗。 假设、具体目标和研究设计：该提案的假设是“S1PR3 加剧” 活性有助于致癌 K-Ras 突变体驱动的 LADC 进展，至少部分是通过促进 巨噬细胞浸润至 LADC。 S1PR3 代表 K-Ras 治疗的潜在治疗靶点 突变体驱动的 LADC。”提出了两个目标来检验这一假设。目标 1. 基因工程小鼠 菌株，表达突变 K-Ras 蛋白且缺乏 S1PR3 的小鼠，将被用来确定关键作用 K-Ras 突变驱动的 LADC 中的 S1PR3。此外，S1PR3 在募集炎症巨噬细胞中的作用 LADC 将接受调查。目标 2. TY-52156，一种高选择性 S1PR3 拮抗剂，将用于证明 概念证明 S1PR3 抑制是对致癌 K-Ras 突变驱动的 LADC 的有效干预措施。 该项目的健康相关性：肺癌仍然是癌症相关死亡的主要原因。主要 该应用的目标是表征 S1PR3 在 K-Ras 突变驱动的 LADC 进展中的关键作用。 本次申请的成功完成，有望为抗击疫情提供多个介入点 未来对抗致癌 K-Ras 突变驱动的 LADC。