Targeting the cholesterol metabolism to treat glioblastoma

描述(申请人提供)：胶质母细胞瘤(GBM)是成人最常见的原发脑瘤，也是所有癌症中最致命的癌症之一，尽管接受了先进的治疗，患者的中位生存期为12-15个月。目前还没有有效的治疗策略来对抗GBM的恶性生长。因此，迫切需要识别新的分子靶点和开发创新的治疗策略。EGFR/PI3K/Akt信号通路在大约88%的GBM患者中被激活，这表明针对这一途径治疗GBM可能是一种有前途的治疗策略。不幸的是，使用其小分子抑制剂靶向EGFR、PI3K和mTOR没有或显示出非常短期的反应。为了显著提高GBM的治疗效果，有必要更好地了解GBM发病的分子机制及其生物学特性。代谢重编程已被证明与致癌生长信号相协调，并促进肿瘤的快速生长。然而，代谢变化的详细机制及其与致癌信号的分子联系仍不清楚。我们先前的研究首次证明，GBM的脂肪酸合成高度增加，并通过激活主要的脂肪生成转录因子-固醇调节元件结合蛋白-1(SREBP-1)而被EGFR/PI3K/Akt信号上调。除了脂肪酸，胆固醇对细胞也很重要，因为它是细胞膜的基本成分。然而，目前尚不清楚癌症患者的胆固醇代谢是否发生了变化。我们的初步数据显示，胆固醇酯和富含胆固醇的低密度脂蛋白受体(LDLR)在GBM细胞系和患者组织中都高度升高，尤其是在表达EGFRvIII的细胞中。我们的数据进一步表明，GBM细胞的生长高度依赖于低密度脂蛋白的摄取，激活核受体肝脏X受体(LXR)显著抑制GBM细胞的生长。这一应用的假设是，GBM细胞的快速生长依赖于胆固醇摄取，其高水平是由EGFR/PI3K/Akt信号通过上调SREBP-1/LDLR途径促进低密度脂蛋白摄取来维持的。我们预测LDLR和LXR是GBM的新的分子靶点，单独或联合抑制脂肪酸合成将显著抑制GBM的生长。在这项研究中，我们旨在寻找一种新的治疗靶向的肿瘤生存途径，并研究靶向LDLR或激活LXR的合成激动剂GW3965和T9091317单独或与FASN抑制剂C75联合应用对GBM移植瘤生长的效果。我们将：1)确定EGFR/PI3K信号上调低密度脂蛋白受体和低密度脂蛋白摄取的分子机制，并测试阿托伐他汀对AIM 1中GBM细胞摄取的作用；2)研究LDLR在AIM 2中对GBM肿瘤生长的作用；3)确定GW3965、T9091317或联合FASN抑制剂C75激活LXR对GBM肿瘤生长的机制和疗效，并评估这些药物治疗AIM 3中GBM的翻译潜力。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor in adults and one of the most lethal of all cancers, with a median patient survival of 12-15 months despite advanced treatment. There is no effective therapeutic strategy to antagonize GBM malignant growth. Therefore, identification of new molecular targets and development of innovative treatment strategies are desperately needed. EGFR/PI3K/Akt signaling has been shown to be activated in around 88% of GBM patients, which suggests that it could be a promising therapeutic strategy to target this pathway to treat GBM. Unfortunately, targeting EGFR, PI3K and mTOR using its small molecular inhibitors has shown no or very short-term response. To significantly improve the efficacy of GBM treatment, it is essential to better understand the underlying molecular mechanisms of GBM pathogenesis and its biologic characteristics. Metabolism reprogramming has been shown to coordinate with oncogenic growth signaling and promote rapid tumor growth. However, the detailed mechanisms of metabolic changes and their molecular links with oncogenic signaling are still unclear. Our previous study was the first to demonstrate that fatty acid synthesis is highly elevated in GBM and is upregulated by EGFR/PI3K/Akt signaling through activation of sterol regulatory element-binding protein-1 (SREBP-1), a master lipogenesis transcriptional factor. In addition to fatty acid cholesterol is also important for cells as it is an essential component of cell membranes. However, whether cholesterol metabolism is altered in cancers remains unknown. Our preliminary data shows that cholesteryl esters and cholesterol-rich low density lipoprotein (LDL) receptor (LDLR) are both highly elevated in GBM cell lines and patient tissues, particularly in EGFRvIII- expressing cells. Our data further demonstrate that GBM cell growth is highly dependent on LDL uptake, and activating nuclear receptor liver X receptor (LXR) significantly inhibits GBM cell growth. The hypothesis of this application is that GBM cells are dependent on cholesterol uptake for rapid growth, and its high levels are maintained by EGFR/PI3K/Akt signaling through upregulation of the SREBP-1/LDLR pathway to promote LDL uptake. We predict that LDLR and LXR are novel molecular targets in GBM and depriving cells of cholesterol alone or in combination with inhibition of fatty acid synthesis will significantly inhiit GBM growth. In this study, we aim to identify a novel therapeutically targetable tumor survival pathway, and investigate the efficacy of targeting LDLR or activating LXR by its synthetic agonists GW3965 and T9091317, separately or in combination with the FASN inhibitor C75 on GBM xenograft tumor growth. We will: 1) determine the molecular mechanism by which EGFR/PI3K signaling upregulates LDLR and LDL uptake, and test atorvastatin treatment in GBM cells in Aim 1; 2) investigate the role of LDLR on GBM tumor growth in Aim 2; 3) determine the mechanism and efficacy of activating LXR by GW3965, T9091317 alone or in combination with FASN inhibitor C75 on GBM tumor growth, and evaluate the translational potential of these drugs to treat GBM in Aim 3.