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的过表达及其突变与大多数非小细胞肺癌有关，并通过促进细胞增殖、细胞运动和细胞存活参与了恶性转化过程。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发挥重要作用。在我们的初步数据中，我们已经证明从植物中提取的大麻素，如d9 -四氢大麻酚，抑制表皮生长因子受体（EGFR）介导的信号传导，合成大麻素，如JWH-133，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，结合CB1/CB2受体的合成大麻素可以作为抑制EGF/ egfr介导和CXCL12/ cxcr4介导的NSCLC生长和转移的新策略。在本研究中，我们将进一步明确合成大麻素对非小细胞肺癌生长和转移的抑制作用。为此，我们将利用转基因和敲除小鼠模型系统的优势，采用创新的多学科方法。在目的1中，我们将分析非小细胞肺癌患者样本中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。在目的2中，我们将在各种动物模型中评估合成大麻素对肺癌生长和转移的特异性潜力。我们将首先分析合成大麻素对SCID小鼠模型系统体内肿瘤生长和转移的影响。此外，我们计划利用CB1和CB2敲除小鼠特异性分析CB1/CB2受体在肺癌进展和转移中的作用。此外，我们建议分析结合CB1和CB2受体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EGFR并促进这些小鼠的肺癌生长。该模型代表了最具疾病相关性的人肺癌模型，以确定合成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介导的非小细胞肺癌生长和转移的分子机制。研究合成大麻素和大麻素受体CB1和CB2的作用，可以为治疗高致死性和化疗耐药的非小细胞肺癌开辟新的治疗策略，考虑到非小细胞肺癌患者预后不良，这一点尤为重要。这项研究可以产生重要的新型临床治疗方法，将显著提高肺癌死亡率和促进肺部健康。

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.