Targeting the cholesterol metabolism to treat glioblastoma

靶向胆固醇代谢治疗胶质母细胞瘤

基本信息

批准号：
9122504
负责人：
Deliang Guo
金额：
$ 33.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122504
关键词：
Adult Agonist Animal Model Biologic Characteristic Biological Availability Biology Brain Glioblastoma Cell Death Cell Line Cell Survival Cell membrane Cells Characteristics Cholesterol Cholesterol Esters Cholesterol Homeostasis Complex DNA Sequence Alteration Data Development Enzymes Epidermal Growth Factor Receptor FRAP1 gene Fatty Acids Fatty-acid synthase Feedback Future Glioblastoma Glycolysis Growth Health In Vitro Investigation Lead Link Lipids Liver X Receptor Low Density Lipoprotein Receptor Low-Density Lipoproteins Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Molecular Molecular Target Nuclear Receptors Oncogenic Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Primary Brain Neoplasms Publishing Radiosurgery Receptor Activation Receptor Protein-Tyrosine Kinases Resistance Role SRE-1 binding protein Signal Pathway Signal Transduction Testing Therapeutic Tissues Treatment Efficacy Up-Regulation Xenograft procedure antitumor effect atorvastatin cancer cell cancer type cell growth deprivation epidermal growth factor receptor VIII improved in vivo inhibitor/antagonist innovation knock-down lipid biosynthesis molecular targeted therapies mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics pre-clinical rapid growth response small hairpin RNA small molecular inhibitor transcription factor treatment strategy tumor tumor growth uptake

项目摘要

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.

描述（由申请人提供）：胶质母细胞瘤（GBM）是成年人中最常见的原发性脑肿瘤，也是所有癌症中最致命的脑肿瘤之一，尽管经过晚期治疗，患者中位患者的中位数为12-15个月。没有有效的治疗策略可以拮抗GBM恶性增长。因此，迫切需要确定新分子靶标和创新治疗策略的发展。 EGFR/PI3K/AKT信号已显示在约88％的GBM患者中被激活，这表明这可能是针对治疗GBM的途径的有希望的治疗策略。不幸的是，使用其小分子抑制剂靶向EGFR，PI3K和MTOR没有显示出或非常短期的反应。为了显着提高GBM治疗的疗效，必须更好地了解GBM发病机理及其生物学特征的潜在分子机制至关重要。已证明代谢重编程可以与致癌生长信号传导进行协调并促进快速肿瘤的生长。但是，代谢变化的详细机制及其与致癌信号的分子联系仍然不清楚。我们先前的研究是第一个证明脂肪酸合成在GBM中的高度升高，并通过激活固醇调节元素结合蛋白-1（SREBP-1）（主脂肪生成转录因子）的激活而被EGFR/PI3K/AKT信号上调。除脂肪酸胆固醇外，对于细胞也很重要，因为它是细胞膜的重要组成部分。但是，癌症中是否改变了胆固醇代谢仍然未知。我们的初步数据表明，在GBM细胞系和患者组织中，尤其是在EGFRVIII-Expressing细胞中，胆固醇酯和富含胆固醇的低密度脂蛋白（LDL）受体（LDLR）都高度升高。我们的数据进一步表明，GBM细胞的生长高度取决于LDL摄取，激活核受体肝X受体（LXR）显着抑制GBM细胞的生长。该应用的假设是，GBM细胞取决于胆固醇的摄取来快速生长，并且通过上调SREBP-1/LDLR途径，通过EGFR/PI3K/AKT信号来维持其高水平，以促进LDL摄取。我们预测，LDLR和LXR是GBM中的新分子靶标，单独或与抑制脂肪酸合成的胆固醇剥夺，将显着吸收GBM的生长。在这项研究中，我们旨在确定一种新型的具有治疗靶向的肿瘤存活途径，并分别或通过其合成激动剂GW3965和T9091317靶向LDLR或激活LXR的功效，或与FASN抑制剂C75结合使用GBM Xenogroftaft tumor的生长。我们将：1）确定EGFR/PI3K信号上调LDLR和LDL摄取的分子机制，并在AIM 1中测试GBM细胞中的Atorvastatin处理； 2）研究LDLR在AIM 2中GBM肿瘤生长的作用； 3）单独使用GW3965，T9091317激活LXR的机制和功效，或与FASN抑制剂C75在GBM肿瘤生长上结合使用，并评估这些药物在AIM 3中治疗GBM的翻译潜力。