Targeting the cholesterol metabolism to treat glioblastoma

靶向胆固醇代谢治疗胶质母细胞瘤

• 批准号: 8506410
• 负责人: Deliang Guo
• 金额: $ 33.68万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8506410
• 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; Data; Development; Enzymes; Epidermal Growth Factor Receptor; Fatty Acids; Fatty-acid synthase; Feedback; Future; Gene Mutation; Glioblastoma; Glycolysis; Growth; In Vitro; Investigation; Lead; Link; Lipids; Liver; 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; atorvastatin; cancer cell; cancer type; cell growth; deprivation; epidermal growth factor receptor VIII; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; innovation; lipid biosynthesis; mouse model; mutant; neoplastic cell; novel; novel therapeutics; pre-clinical; public health relevance; rapid growth; receptor; response; small hairpin RNA; transcription factor; treatment strategy; tumor; tumor growth; uptake

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）是成人中最常见的原发性脑肿瘤，也是所有癌症中最致命的肿瘤之一，尽管进行了晚期治疗，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恶性生长。因此，迫切需要鉴定新的分子靶点和开发创新的治疗策略。EGFR/PI 3 K/Akt信号通路在约88%的GBM患者中被激活，这表明靶向该通路治疗GBM可能是一种有前景的治疗策略。不幸的是，使用其小分子抑制剂靶向EGFR、PI 3 K和mTOR没有显示出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发病机制及其生物学特性的潜在分子机制。代谢重编程已被证明与致癌生长信号传导协调并促进肿瘤快速生长。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。我们之前的研究首次证明GBM中脂肪酸合成高度升高，并且通过激活固醇调节元件结合蛋白-1（SREBP-1）（一种主要的脂肪生成转录因子），由EGFR/PI 3 K/Akt信号转导上调。除了脂肪酸，胆固醇对细胞也很重要，因为它是细胞膜的重要组成部分。然而，胆固醇代谢是否在癌症中改变仍然未知。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（LDL）受体（LDLR）在GBM细胞系和患者组织中均高度升高，特别是在EGFRvIII表达细胞中。我们的数据进一步证明GBM细胞生长高度依赖于LDL摄取，并且激活核受体肝X受体（LXR）显著抑制GBM细胞生长。本申请的假设是，GBM细胞依赖于胆固醇摄取以快速生长，并且其高水平通过EGFR/PI 3 K/Akt信号传导通过上调SREBP-1/LDLR途径以促进LDL摄取来维持。我们预测LDLR和LXR是GBM中的新分子靶点，单独剥夺细胞胆固醇或与抑制脂肪酸合成相结合将显著抑制GBM生长。在这项研究中，我们的目的是确定一种新的治疗靶向肿瘤生存途径，并研究靶向LDLR或激活LXR的合成激动剂GW 3965和T9091317，单独或与FXR抑制剂C75对GBM异种移植肿瘤生长的疗效。我们将：1）确定EGFR/PI 3 K信号传导上调LDLR和LDL摄取的分子机制，并在Aim 1中测试GBM细胞中的阿托伐他汀治疗; 2）在Aim 2中研究LDLR对GBM肿瘤生长的作用; 3）确定单独或与FXR抑制剂C75组合的GW 3965、T9091317激活LXR对GBM肿瘤生长的机制和功效，并评估这些药物治疗目的3中GBM的转化潜力。