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Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy

靶向甾醇基因 SC4MOL 和 EGFR 作为协同抗癌策略

基本信息

批准号：
8723411
负责人：
Igor Astsaturov
金额：
$ 19.6万
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：
2013
资助国家：
美国
起止时间：
2013-07-03 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723411
关键词：
Address Animal Model Bioinformatics Cancer Cell Growth Cancer cell line Carcinogens Cell Culture Techniques Cell membrane Cells Cetuximab Chemotherapy-Oncologic Procedure Chloroquine Cholesterol Collaborations Data Distal Doctor of Medicine Doctor of Philosophy Drug Targeting Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Epithelial Cells ErbB Receptor Family Protein Erlotinib Eukaryota Family member Gene Expression Regulation Genes Goals Growth HRAS gene In Vitro Ketoconazole Knock-out Knockout Mice Knowledge Letters Ligands Link Literature Lysosomes Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Modeling Mus NADP Oxidases Oxidoreductase Pathway interactions Preclinical Testing Predisposition Primaquine Process Proteins Public Health Publishing Reaction Receptor Signaling Recycling Regulation Role Science Signal Transduction Small Interfering RNA Sorting - Cell Movement Steroids Sterol Biosynthesis Pathway Sterols Stratum Basale Testing Transition Career Development Award (K22)Work abstracting base cancer cell cancer chemoprevention cancer therapy carcinogenesis cholesterol biosynthesis clinically relevant demethylation desensitization dimethylbenzanthracene drug development improved in vivo inhibitor/antagonist keratinocyte mouse model neoplastic cell novel protein function receptor receptor internalization response small hairpin RNA trafficking tumor tumor xenograft

项目摘要

Abstract Epidermal growth factor receptor (EGFR) has been heavily exploited as a target for blockade in cancer therapy. In normal epithelial cells, ligand-induced internalization of activated receptors and their sorting for degradation in lysosomes is the limiting mechanism for EGFR signaling. This desensitization process is commonly circumvented by cancer cells to promote their growth and survival even in the presence of EGFR signaling inhibitors. We have identified a novel role for the sterol biosynthesis pathway to influence this recycling process which could significantly improve the efficacy of EGFR-targeting inhibitors. Silencing of SC4MOL (sterol C4-methyl oxidase-like) significantly sensitizes tumor cells to EGFR inhibitors using a network-guided siRNA-based screen (Astsaturov, 2010). We have determined that SC4MOL and a functionally linked partner protein, NSDHL (NADP-dependent steroid dehydrogenase-like), are negative regulators of trafficking of EGFR and its family members ErbB2 and ErbB3 from the plasma membrane to the lysosome for destruction. Our central hypothesis is that metabolic blockade of the sterol biosynthesis pathway will accelerate receptor degradation and thus suppress EGFR signaling in vitro; in NSDHL conditional knockout mice, this will limit epithelial carcinogenesis. Our immediate objective is to validate a new metabolic target for cancer therapy involving these previously unexplored genes in the distal sterol biosynthesis pathway. With the strong team of collaborators assembled, we propose the following 3 specific Aims: Aim 1. Investigate the mechanism of EGFR signaling regulation by genes in the sterol biosynthesis pathway. On the basis of preliminary data and complementary bioinformatic analysis, we hypothesize that blockade of SC4MOL and NSDHL causes altered EGFR trafficking that accelerates EGFR degradation in lysosomes. Aim 2. Determine the value of combined targeting of SC4MOL and EGFR in tumor xenografts. Based on our preliminary in vitro data, we propose that shRNA silencing of SC4MOL will increase the response of tumor xenografts to EGFR blockade. Aim 3. Investigate in vivo effects of sterol pathway on EGFR signaling and susceptibility to carcinogens. We hypothesize that the EGFR-antagonistic effects of the epithelial NSDHL deficiency will limit the H-Ras-dependent or -independent carcinogenesis. This proposal is significant because it will provide fundamentally new knowledge on how the metabolism of sterols regulates signaling activity of essential cancer receptors such as EGFR. We believe that pharmacological inhibition of sterol pathway targets such as SC4MOL and NSDHL has the potential for cancer chemotherapy and chemoprevention as an entirely novel class of agents.

摘要表皮生长因子受体（EGFR）已被大量开发作为癌症阻断的靶点疗法在正常上皮细胞中，配体诱导的活化受体的内化和它们的分选，溶酶体中的降解是EGFR信号传导的限制机制。这种脱敏过程是即使在EGFR存在的情况下，癌细胞通常也会绕过这些屏障，以促进其生长和存活信号传导抑制剂我们已经确定了一个新的作用，甾醇生物合成途径，以影响这一点，回收过程，可以显着提高EGFR靶向抑制剂的疗效。沉默 SC 4 MOL（固醇C4-甲基氧化酶样）使用EGFR抑制剂显着增敏肿瘤细胞，基于网络引导的siRNA筛选（Astsaturov，2010）。我们已经确定，SC 4 MOL和功能性连接伴侣蛋白NSDHL（NADP依赖性类固醇脱氢酶样）为阴性 EGFR及其家族成员ErbB 2和ErbB 3从质膜转运至细胞膜的调节因子溶酶体的破坏。我们的中心假设是代谢阻断甾醇生物合成途径将加速受体降解，从而在体外抑制EGFR信号传导;在NSDHL条件性敲除中小鼠，这将限制上皮癌发生。我们的近期目标是验证一个新的代谢目标，癌症治疗涉及这些以前未开发的基因在远端甾醇生物合成途径。在强大的合作者团队的帮助下，我们提出了以下三个具体目标：目标1。探讨固醇生物合成中EGFR信号转导的基因调控机制通路根据初步数据和补充生物信息学分析，我们假设，阻断SC 4 MOL和NSDHL可导致EGFR转运改变，从而加速EGFR降解。溶酶体目标二。确定SC 4 MOL和EGFR在肿瘤异种移植物中的联合靶向价值。基于我们初步的体外实验数据，我们提出SC 4 MOL的shRNA沉默将增加SC 4 MOL的表达。肿瘤异种移植物对EGFR阻断的反应。目标3.研究固醇途径对EGFR信号传导和对EGFR敏感性的体内影响。致癌物质。我们假设上皮NSDHL缺陷的EGFR拮抗作用将限制 H-Ras依赖或非依赖致癌作用。这一建议是重要的，因为它将提供关于如何代谢的新知识。固醇调节必需的癌症受体如EGFR的信号传导活性。我们认为固醇途径靶点如SC 4 MOL和NSDHL的药理学抑制具有潜在的癌症化学疗法和化学预防作为一种全新的药剂。