Synthetic cannabinoids as novel therapeutic strategies against non-small cell lun

合成大麻素作为非小细胞肺癌的新型治疗策略

• 批准号: 8206385
• 负责人: Ramesh K. Ganju
• 金额: $ 19.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206385
• 关键词: Accounting; Agonist; Animal Model; Binding; Biological Models; CNR1 gene; CNR2 gene; CXCL12 gene; CXCR4 gene; Cancer Patient; Cancer cell line; Cannabinoids; Cell Proliferation; Cell Survival; Cells; Clinical; Clinical Trials; Data; Development; Disease; Disease-Free Survival; Drug resistance; EGF gene; EGFR Protein Overexpression; Epidermal Growth Factor Receptor; FOXO3A gene; Focal Adhesion Kinase 1; Focal Adhesions; Future; Genetically Engineered Mouse; Growth; Health; Human; Immune; In Vitro; Investigation; Knockout Mice; Lewis Lung Carcinoma; Ligands; Lung; Malignant - descriptor; Malignant Epithelial Cell; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Plants; Play; Process; Property; Receptor Signaling; Reporting; Research; Resistance; Role; SCID Mice; Safety; Sampling; Signal Transduction; Stress Fibers; T-Lymphocyte; Targeted Research; Tetanus Helper Peptide; Tetrahydrocannabinol; Therapeutic; Transgenic Mice; Transgenic Organisms; Work; cancer stem cell; cell motility; chemokine receptor; chemotherapy; improved; in vivo; innovation; insight; interdisciplinary approach; malignant breast neoplasm; migration; mortality; mouse model; mutant; novel; novel strategies; novel therapeutics; outcome forecast; overexpression; receptor; receptor-mediated signaling; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Furthermore, overexpression of EGFR and its mutation are associated with the majority of NSCLCs and have been implicated in the process of malignant transformation by promoting cell proliferation, cell motility and cell survival. Recently, chemokine receptor CXCR4 and its ligand CXCL12 have been shown to play an important role in lung cancer progression and metastasis. In our preliminary data, we have shown that cannabinoids derived from plants, such as D9-tetrahydrocannabinol, inhibit epidermal growth factor receptor (EGFR)-mediated signaling and synthetic cannabinoids, such as JWH-133, inhibit CXCR4-mediated signaling. Cannabinoids have been shown to mediate their effects through cannabinoid receptors CB1 and CB2. Therefore, our central hypothesis is that synthetic cannabinoids that bind to CB1/CB2 receptors could be used as novel strategies to inhibit EGF/EGFR-mediated and CXCL12/CXCR4-mediated growth and metastasis in NSCLC. In this proposal, we will further define the inhibitory properties of synthetic cannabinoids against NSCLC growth and metastasis. To this end, we will use an innovative multidisciplinary approach by taking advantage of transgenic and knockout mouse model systems. In aim 1, we will analyze the expression of CB1 and CB2 receptors in NSCLC patient samples. We will also analyze the role of synthetic cannabinoids against EGF/EGFR and CXCL12/CXCR4-induced growth and migration of NSCLC cell lines. In aim 2, we will evaluate the specific potential of synthetic cannabinoids against lung cancer growth and metastasis in various animal models. We will first analyze the effect of synthetic cannabinoids on tumor growth and metastasis in vivo in SCID mouse model systems. Furthermore, we plan to use CB1 and CB2 knockout mice to specifically analyze the role of CB1/CB2 receptors in lung cancer progression and metastasis. In addition, we propose to analyze the effect of synthetic cannabinoids that bind to CB1 and CB2 receptors on a genetically engineered mouse model system that overexpresses mutant EGFR and enhances lung cancer growth in these mice. This model represents the most disease- relevant model of human lung cancer to determine the anti-tumorigenic effects of synthetic CB1/CB2 agonists. We expect that the use of different animal model systems will help us clarify the therapeutic potential of synthetic cannabinoids against NSCLC. Finally, in aim 3, we will delineate the synthetic cannabinoid-induced and CB1/CB2-mediated molecular mechanisms that inhibit EGFR and CXCR4- mediated growth and metastasis of NSCLC. This investigation on the role of synthetic cannabinoids and cannabinoid receptors CB1 and CB2 can open new therapeutic strategies toward the treatment of highly-fatal and chemo-resistant NSCLC, which is especially imperative considering the poor prognosis of NSCLC patients. The proposed research can yield important novel future clinical therapies that will significantly improve lung cancer mortality and promote lung health. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Overexpression of EGFR and chemokine receptor CXCR4 has been implicated in promoting NSCLC tumor growth and metastasis. We are proposing that synthetic cannabinoids that bind to cannabinoid receptors (CB1 and CB2) may inhibit NSCLC growth and metastasis by blocking epidermal growth factor receptor (EGFR) and/or chemokine receptor CXCR4 signaling. Therefore, understanding the cannabinoid-induced tumor-suppressive mechanism and determining the clinical utility of synthetic cannabinoids will aid in the development of novel strategies against highly fatal and chemo-resistant NSCLC. Furthermore, synthetic cannabinoids, with their favorable drug safety profile, could become novel targets in clinical trials resulting in a relatively quick transition from lab to bedside.

描述（由申请人提供）：非小细胞肺癌 (NSCLC) 占肺癌病例的 85%。此外，EGFR 的过度表达及其突变与大多数 NSCLC 相关，并通过促进细胞增殖、细胞运动和细胞存活参与恶性转化过程。最近，趋化因子受体CXCR4及其配体CXCL12被证明在肺癌进展和转移中发挥重要作用。在我们的初步数据中，我们已经表明，源自植物的大麻素（例如 D9-四氢大麻酚）可抑制表皮生长因子受体（EGFR）介导的信号传导，而合成大麻素（例如 JWH-133）可抑制 CXCR4 介导的信号传导。大麻素已被证明通过大麻素受体 CB1 和 CB2 介导其作用。因此，我们的中心假设是，与 CB1/CB2 受体结合的合成大麻素可用作抑制 NSCLC 中 EGF/EGFR 介导和 CXCL12/CXCR4 介导的生长和转移的新策略。在本提案中，我们将进一步定义合成大麻素对 NSCLC 生长和转移的抑制特性。为此，我们将利用转基因和基因敲除小鼠模型系统，采用创新的多学科方法。在目标 1 中，我们将分析 NSCLC 患者样本中 CB1 和 CB2 受体的表达。我们还将分析合成大麻素对 EGF/EGFR 和 CXCL12/CXCR4 诱导的 NSCLC 细胞系生长和迁移的作用。在目标 2 中，我们将评估合成大麻素在各种动物模型中对抗肺癌生长和转移的具体潜力。我们将首先在 SCID 小鼠模型系统中分析合成大麻素对体内肿瘤生长和转移的影响。此外，我们计划使用CB1和CB2基因敲除小鼠来专门分析CB1/CB2受体在肺癌进展和转移中的作用。此外，我们建议分析与 CB1 和 CB2 受体结合的合成大麻素对基因工程小鼠模型系统的影响，该系统过度表达突变 EGFR 并增强这些小鼠的肺癌生长。该模型代表了与人类肺癌疾病最相关的模型，用于确定合成 CB1/CB2 激动剂的抗肿瘤作用。我们期望使用不同的动物模型系统将有助于我们阐明合成大麻素对非小细胞肺癌的治疗潜力。最后，在目标 3 中，我们将描述合成大麻素诱导和 CB1/CB2 介导的抑制 EGFR 和 CXCR4 介导的 NSCLC 生长和转移的分子机制。这项关于合成大麻素和大麻素受体 CB1 和 CB2 作用的研究可以为治疗高致命性和化疗耐药的 NSCLC 开辟新的治疗策略，考虑到 NSCLC 患者的不良预后，这一点尤其重要。拟议的研究可以产生重要的新型未来临床疗法，将显着降低肺癌死亡率并促进肺部健康。 公共卫生相关性：非小细胞肺癌 (NSCLC) 约占肺癌病例的 85%。 EGFR 和趋化因子受体 CXCR4 的过度表达与促进 NSCLC 肿瘤的生长和转移有关。我们提出，与大麻素受体（CB1 和 CB2）结合的合成大麻素可以通过阻断表皮生长因子受体（EGFR）和/或趋化因子受体 CXCR4 信号传导来抑制 NSCLC 生长和转移。因此，了解大麻素诱导的肿瘤抑制机制并确定合成大麻素的临床用途将有助于开发针对高度致命和化疗耐药的非小细胞肺癌的新策略。此外，合成大麻素凭借其良好的药物安全性，可能成为临床试验中的新靶标，从而相对较快地从实验室过渡到临床。