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：
8930103
负责人：
Igor Astsaturov
金额：
$ 37.04万
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/8930103
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Address Affect Anabolism Antibodies Apolipoprotein E Bioinformatics Cancer Cell Growth 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 Erlotinib Family member Genetic Genetic Models Germ Cells Goals Gonadal structure Growth Head and Neck Cancer Head and neck structure Health Human KRAS2 gene LDL Cholesterol Lipoproteins Libraries Link Liver Low Density Lipoprotein Receptor Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Meiosis Membrane Metabolic Metabolism Mus NADP Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Oxidases Oxidoreductase Pathway interactions Pharmaceutical Preparations Proteins Receptor Signaling Regulatory Element Resistance Role Series Signal Pathway Signal Transduction Small Interfering RNA Steroids Sterol Biosynthesis Pathway Sterols System TP53 gene Testing Translating United States Work Xenograft procedure angiogenesis base cancer cell cell growth cell motility compactin enzyme substrate improved in vivo inhibitor/antagonist mevalonate mouse model mutant neoplastic cell novel premature protein function receptor receptor function research study 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）及其家族成员的持续活性是癌症生长和耐药性的常见原因。在一系列生物信息学指导的 siRNA 文库筛选实验中，我们鉴定了一个影响耐药性的蛋白质网络，其中包括 SC4MOL（类甾醇 C4 甲基氧化酶），这是甾醇生物合成途径中一种很少被研究的中间酶（Astsaturov，2010）。我们的工作是第一个研究癌症中的 SC4MOL 和 NSDHL (Sukhanova, 2013)，我们建立了癌症中 EGFR 信号传导和甾醇代谢之间的相互作用，旨在为提高靶向治疗的疗效提供新的机会。我们发现，沉默 SC4MOL 或 NSDHL，或直接添加减数分裂激活甾醇 (MAS)（这些酶的底物），可以显着提高癌细胞对 EGFR 抑制剂的敏感性（Sukhanova，2013）。我们还发现，在 SC4MOL 或 NSDHL 水平上抑制甾醇途径会激活肝脏 X 受体 (LXR)，从而诱导胆固醇流出蛋白（ABC 转运蛋白 ABCA1 和 ABCG1）的表达，消耗细胞胆固醇，并减少胆固醇外流蛋白的表达。 LDL 脂蛋白受体（LDLR）。令人兴奋的是，我们发现 SC4MOL 或 NSDHL 的缺失与针对人类异种移植物的抗 EGFR 抗体西妥昔单抗具有深刻的协同作用，并在小鼠遗传模型中抑制 KRAS 驱动的肿瘤的生长。我们的中心假设是，MAS 甾醇代谢物因 SC4MOL 或 NSDHL 缺陷而积累，并通过激活 LXR、破坏胆固醇摄取和生物合成以及抑制致癌 EGFR-KRAS 信号传导来负向调节细胞生长。我们将通过执行以下具体目标来解决这一假设：在目标 1 中，我们将确定 SC4MOL 和 NSDHL 的代谢底物调节胆固醇稳态并有助于癌细胞对 EGFR 抑制剂的敏感性的机制。在目标 2 中，我们将使用 NSDHL 缺陷的遗传小鼠模型来确定 SC4MOL、NSDHL 及其底物如何调节正常细胞与 EGFR 依赖性癌细胞的生长。在目标 3 中，我们将测试相关假设，即加速胆固醇代谢决定癌症的侵袭性和 EGFR 靶向治疗的难治性，并且通过 LXR 联合靶向 EGFR 信号传导和胆固醇代谢将具有协同作用。该项目将阐明调节 EGFR 功能的全新机制。最理想的情况是，这项工作将证明靶向 SC4MOL、NSDHL 或 MAS 甾醇下游其他新靶点将有益于广泛的 EGFR 阳性人类癌症，包括头颈癌和胰腺癌。