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

描述(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有关，并通过促进细胞增殖、细胞运动和细胞存活而参与了NSCLC的恶变过程。近年来，趋化因子受体CXCR4及其配体CXCL12被证明在肺癌的进展和转移中起重要作用。在我们的初步数据中，我们已经表明，从植物中提取的大麻素，如D9-四氢大麻酚，可以抑制表皮生长因子受体(EGFR)介导的信号转导；合成的大麻素，如JWH-133，可以抑制CXCR4介导的信号转导。大麻素已被证明通过大麻素受体CB1和CB2来调节其作用。因此，我们的中心假设是，合成的与CB1/CB2受体结合的大麻素可以作为新的策略来抑制EGF/EGFR和CXCL12/CXCR4介导的NSCLC的生长和转移。在这项提案中，我们将进一步定义合成大麻素对非小细胞肺癌生长和转移的抑制特性。为此，我们将使用一种创新的多学科方法，利用转基因和基因敲除小鼠模型系统。在目的1中，我们将分析CB1和CB2受体在NSCLC患者标本中的表达。我们还将分析合成的大麻素对EGF/EGFR和CXCL12/CXCR4诱导的非小细胞肺癌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不同动物模型中抑制肺癌生长和转移的特异性潜力。我们将首先在SCID小鼠模型系统中分析合成大麻素对肿瘤生长和转移的影响。此外，我们计划使用CB1和CB2基因敲除小鼠来具体分析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，该模型系统过度表达突变的EGFR并促进这些小鼠的肺癌生长。该模型代表了与疾病最相关的人类肺癌模型，以确定合成的CB1/CB2激动剂的抗肿瘤作用。我们期望不同的动物模型系统的使用将有助于我们阐明合成大麻类化合物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介导的非小细胞肺癌生长和转移的分子机制。研究合成大麻素及其受体CB1和CB2的作用，可以为治疗高度致命性和化疗耐药的非小细胞肺癌开辟新的治疗策略，尤其是考虑到非小细胞肺癌患者的不良预后。这项拟议的研究可以产生重要的新的未来临床疗法，这些疗法将显着提高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NSCLC肿瘤的生长和转移密切相关。我们认为，与大麻素受体(CB1和CB2)结合的合成大麻素可能通过阻断表皮生长因子受体(EGFR)和/或趋化因子受体CXCR4信号来抑制NSCLC的生长和转移。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应用将有助于开发针对高致命性和耐药的非小细胞肺癌的新策略。此外，合成大麻素具有良好的药物安全性，可以成为临床试验的新靶点，从而相对较快地从实验室过渡到床边。

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.