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.

抽象的表皮生长因子受体 (EGFR) 已被广泛用作癌症阻断的靶标治疗。在正常上皮细胞中，配体诱导激活受体的内化及其分类溶酶体的降解是 EGFR 信号传导的限制机制。这个脱敏过程是即使在 EGFR 存在的情况下，癌细胞通常也会绕过这些途径来促进其生长和存活信号传导抑制剂。我们已经确定了甾醇生物合成途径的一个新作用来影响这一点回收过程可以显着提高EGFR靶向抑制剂的功效。沉默 SC4MOL（甾醇 C4 甲基氧化酶样）使用以下方法显着使肿瘤细胞对 EGFR 抑制剂敏感基于网络引导的 siRNA 筛选（Astsaturov，2010）。我们已经确定 SC4MOL 和功能性连接伴侣蛋白 NSDHL（NADP 依赖性类固醇脱氢酶样）呈阴性 EGFR 及其家族成员 ErbB2 和 ErbB3 从质膜运输到细胞膜的调节因子溶酶体进行破坏。我们的中心假设是甾醇生物合成途径的代谢阻断将加速受体降解，从而抑制体外 EGFR 信号传导；在 NSDHL 条件性敲除中小鼠，这将限制上皮癌的发生。我们的近期目标是验证新的代谢目标癌症治疗涉及远端甾醇生物合成途径中这些先前未探索的基因。凭借强大的合作团队，我们提出以下 3 个具体目标：目的1.研究甾醇生物合成中基因对EGFR信号传导的调控机制途径。根据初步数据和补充生物信息学分析，我们假设 SC4MOL 和 NSDHL 的阻断会导致 EGFR 运输改变，从而加速 EGFR 降解溶酶体。目标 2. 确定 SC4MOL 和 EGFR 联合靶向在肿瘤异种移植物中的价值。根据我们的初步体外数据，我们建议 SC4MOL 的 shRNA 沉默会增加肿瘤异种移植物对 EGFR 阻断的反应。目标 3. 研究甾醇途径对 EGFR 信号传导和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 依赖性或非依赖性致癌作用。该提案意义重大，因为它将提供关于新陈代谢如何进行的全新知识。甾醇调节重要癌症受体（例如 EGFR）的信号传导活性。我们相信甾醇途径靶点（例如 SC4MOL 和 NSDHL）的药理学抑制具有治疗癌症的潜力化疗和化学预防作为一类全新的药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular Pathways Molecular Pathways : Sterols and Receptor Signaling in Cancer

分子通路分子通路：癌症中的甾醇和受体信号传导

DOI：
10.3390/ijms25042003
发表时间：
2024-09-13
期刊：
International Journal of Molecular Sciences
影响因子：
5.6
作者：
L. Gabitova;A. Gorin;I. Astsaturov
通讯作者：
I. Astsaturov

Successful imatinib therapy for neuroendocrine carcinoma with activating Kit mutation: a case study.

伊马替尼成功治疗具有激活 Kit 突变的神经内分泌癌：案例研究。

DOI：
发表时间：
2014-06
期刊：
影响因子：
0
作者：
Perkins, James;Boland, Patrick;Cohen, Steven J;Olszanski, Anthony J;Zhou, Yan;Engstrom, Paul;Astsaturov, Igor
通讯作者：
Astsaturov, Igor

Regulation of cholesterol biosynthesis and cancer signaling.

胆固醇生物合成和癌症信号传导的调节。