Synergistic targeting of cholesterol metabolism and EGFR signaling in cancer

癌症中胆固醇代谢和 EGFR 信号传导的协同靶向

基本信息

批准号：
9335800
负责人：
Igor Astsaturov
金额：
$ 37.97万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335800
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Address Affect Anabolism Apolipoprotein E Bioinformatics Cancer Etiology Carcinoma Cells Cessation of life Cetuximab Cholesterol Cholesterol Homeostasis Clinic Drug resistance Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family member Fc Receptor Genetic Genetic Models Genetic Transcription Germ Cells Goals Gonadal structure Growth Head Cancer Head and neck structure Human KRAS2 gene Libraries Link Liver X Receptor Low Density Lipoprotein Receptor Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Meiosis Membrane Metabolic Metabolism Mus NADP Neck Cancer Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Oxidases Oxidoreductase Pathway interactions Pharmaceutical Preparations Pharmacology Proteins Receptor Signaling Refractory Regulatory Element Resistance Role Series Signal Pathway Signal Transduction Small Interfering RNA Steroids Sterol Biosynthesis Pathway Sterols System TP53 gene Testing Therapeutic Translating United States Work Xenograft procedure base cancer cell cell growth enzyme substrate experimental study improved in vivo inhibitor/antagonist mouse model mutant neoplastic cell novel premature protein function public health relevance receptor function resistance mechanism screening targeted cancer therapy targeted treatment trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Persistent activity of epidermal growth factor receptor (EGFR) and its family members is a common cause for cancer growth and drug resistance. In a series of bioinformatics-guided siRNA library screening experiments we identified a network of resistance-influencing proteins that included SC4MOL (sterol C4-methyl oxidase-like), a little-studied intermediate enzyme in the sterol biosynthesis pathway (Astsaturov, 2010). Our work is the first to study SC4MOL and NSDHL in cancer (Sukhanova, 2013), and our establishment of reciprocal interactions between EGFR signaling and sterol metabolism in cancer are intended to provide new opportunities to improve the efficacy of targeted therapies. We have found that silencing of SC4MOL or NSDHL, or direct addition of meiosis activating sterols (MAS), a substrate for these enzymes, markedly sensitizes cancer cells to EGFR inhibitors (Sukhanova, 2013). We have also found that arrest of the sterol pathway at the level SC4MOL or NSDHL activates the liver X receptor (LXR), which induces the expression of cholesterol efflux proteins (the ABC transporters ABCA1 and ABCG1), depletes cellular cholesterol, and reduces expression of LDL lipoprotein receptors (LDLR). Excitingly, we found that loss of SC4MOL or NSDHL was profoundly synergistic with the anti-EGFR antibody cetuximab against human xenografts, and suppressed growth of KRAS-driven tumors in a mouse genetic model. Our central hypothesis is that MAS sterol metabolites accumulate as the result of SC4MOL or NSDHL deficiency and negatively regulate cell growth by activating LXR, disrupting cholesterol uptake and biosynthesis, and suppressing oncogenic EGFR-KRAS signaling. We will address this hypothesis by performing the following specific Aims: In Aim 1, we will determine the mechanism by which metabolic substrates of SC4MOL and NSDHL regulate cholesterol homeostasis and contribute to the sensitivity of cancer cells to agents inhibiting EGFR. In Aim 2, we will use a genetic mouse model of NSDHL deficiency to determine how SC4MOL, NSDHL, and their substrates regulate the growth of normal cells versus EGFR-dependent cancer cells. In Aim 3, we will test the linked hypotheses that accelerated cholesterol metabolism defines cancers' aggressiveness and refractoriness to EGFR-targeting therapies, and that combined targeting of EGFR signaling and cholesterol metabolism via LXR will be synergistic. This project will illuminate an entirely new mechanism for regulating EGFR function. Optimally, this work will justify the idea that targeting SC4MOL, NSDHL or additional new targets downstream of MAS sterols would be beneficial for a broad spectrum of EGFR-positive human carcinomas including head and neck and pancreatic cancers.

描述（由申请人提供）：表皮生长因子受体（EGFR）及其家人的持续活动是癌症生长和耐药性的常见原因。在一系列生物信息学引导的siRNA库筛选实验中，我们确定了包括SC4MOL（固醇C4-甲基氧化酶样）的抗性影响蛋白网络，该网络是固醇生物合成途径中的一个有点研究的中间酶（Astsatsaturov，2010年）。我们的工作是第一个研究癌症中SC4mol和NSDHL的工作（Sukhanova，2013年），我们在癌症中建立了EGFR信号传导和固醇代谢之间的相互相互作用，旨在提供新的机会来提高目标疗法的效率。我们发现，SC4MOL或NSDHL的沉默，或直接添加这些酶的固醇激活固醇（MAS）的减数分裂，这些酶的底物显着使癌细胞对EGFR抑制剂敏感（Sukhanova，2013年）。我们还发现，在SC4MOL或NSDHL水平的固醇途径的停滞会激活肝X受体（LXR），该肝脏X受体（LXR）诱导胆固醇外排蛋白的表达（ABC转运蛋白ABCA1和ABCG1），耗尽了细胞胆固醇，并降低了胆固醇的表达，并降低了胆固醇的表达。 LDL脂蛋白受体（LDLR）。令人兴奋的是，我们发现SC4MOL或NSDHL的损失与针对人异种移植物的抗EGFR抗体西妥昔单抗具有深刻的协同作用，并且在小鼠遗传模型中抑制了KRAS驱动的肿瘤的生长。我们的中心假设是，MAS固醇代谢产物因SC4MOL或NSDHL缺乏症而积累，并通过激活LXR，破坏胆固醇的摄取和生物合成，并抑制致癌性EGFR-KRAS信号传导，从而累积。我们将通过执行以下特定目的来解决这一假设：在AIM 1中，我们将确定SC4MOL和NSDHL代谢底物调节胆固醇稳态的机制，并有助于癌细胞对抑制EGFR的药物的敏感性。在AIM 2中，我们将使用NSDHL缺乏症的遗传小鼠模型来确定SC4MOL，NSDHL及其底物如何调节正常细胞的生长与EGFR依赖性癌细胞的生长。在AIM 3中，我们将测试加速胆固醇代谢的链接假设，定义了癌症对EGFR靶向疗法的侵略性和耐火性，以及EGFR信号传导和通过LXR代谢的靶向靶向将是同性恋的。该项目将阐明一种调节EGFR功能的全新机制。最佳地，这项工作将证明以下想法是，将MAS固醇下游的SC4mol，NSDHL或其他新目标靶向将对广泛的EGFR阳性人癌（包括头部和颈部和胰腺癌）有益。