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：
8165559
负责人：
Igor Astsaturov
金额：
$ 19.92万
依托单位：
FOX CHASE CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8165559
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 Critiques Data Distal Doctor of Medicine Doctor of Philosophy Drug Delivery Systems 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 Individual 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 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 Writing base cancer cell cancer chemoprevention cancer therapy carcinogenesis cholesterol biosynthesis clinically relevant demethylation desensitization dimethylbenzanthracene drug development improved in vivo inhibitor/antagonist keratinocyte meetings mouse model neoplastic cell novel protein function receptor receptor internalization response small hairpin RNA trafficking tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): 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 bioinformatics 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. PUBLIC HEALTH RELEVANCE: The NCI Transition Career Development Award (K22) submitted by Igor Astsaturov, M.D., Ph.D. proposes to study a novel cancer-relevant target in the sterol metabolic pathway regulating EGFR signaling. The project titled "Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy" will provide fundamentally new knowledge on how the blockade of sterol metabolism can suppress activity and accelerate degradation of essential cancer receptors such as EGFR. We believe that pharmacological inhibition of sterol pathway targets, SC4MOl and associated NSDHL, has the potential to provide the basis for cancer chemotherapy and chemoprevention with an entirely novel class of agents. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

描述（由申请人提供）：表皮生长因子受体（EGFR）已被广泛用作癌症治疗中的阻断靶点。在正常上皮细胞中，配体诱导的激活受体的内化及其在溶酶体中降解的分类是 EGFR 信号转导的限制机制。即使存在 EGFR 信号抑制剂，癌细胞通常也会绕过这种脱敏过程，以促进其生长和存活。我们已经确定了甾醇生物合成途径对影响这一回收过程的新作用，这可以显着提高 EGFR 靶向抑制剂的功效。使用基于网络引导的 siRNA 筛选，沉默 SC4MOL（甾醇 C4 甲基氧化酶样）可显着提高肿瘤细胞对 EGFR 抑制剂的敏感性（Astsaturov，2010）。我们已经确定 SC4MOL 和功能性连接的伴侣蛋白 NSDHL（NADP 依赖性类固醇脱氢酶样）是 EGFR 及其家族成员 ErbB2 和 ErbB3 从质膜运输到溶酶体进行破坏的负调节因子。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 条件性敲除小鼠中，这将限制上皮癌的发生。我们的直接目标是验证癌症治疗的新代谢靶点，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，我们提出了以下3个具体目标：目标1. 研究甾醇生物合成途径中基因对EGFR信号传导的调控机制。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 运输发生改变，从而加速 EGFR 在溶酶体中的降解。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 沉默将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 信号传导和致癌物敏感性的体内影响。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。这项提议意义重大，因为它将提供关于甾醇代谢如何调节 EGFR 等重要癌症受体的信号活性的全新知识。我们相信，对 SC4MOL 和 NSDHL 等甾醇途径靶标的药理抑制具有作为一类全新药物用于癌症化疗和化学预防的潜力。公共卫生相关性：由 Igor Astsaturov 医学博士、博士提交的 NCI 过渡职业发展奖 (K22)提议研究调节 EGFR 信号转导的甾醇代谢途径中的一个新的癌症相关靶点。该项目名为“以甾醇基因 SC4MOL 和 EGFR 为协同抗癌策略”，将提供关于阻断甾醇代谢如何抑制 EGFR 等重要癌症受体的活性并加速其降解的全新知识。我们相信，甾醇途径靶标SC4M01和相关NSDHL的药理学抑制有可能为癌症化疗和采用全新类型的药剂进行化学预防提供基础。下面的“评论”部分以基本上未经编辑的形式提供了个人评论者的书面评论和标准分数。请注意，这些批评和标准分数是在会议之前准备的，在审查会议上进行任何讨论后可能不会进行修改。上面的“讨论简历和摘要”部分总结了委员会的最终意见。