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

描述（由申请人提供）：表皮生长因子受体（EGFR）已被大量用作癌症治疗中的阻断靶点。在正常上皮细胞中，配体诱导的活化受体内化及其在溶酶体中的降解分选是EGFR信号传导的限制机制。这种脱敏过程通常被癌细胞绕过，以促进其生长和存活，即使在EGFR信号传导抑制剂存在的情况下。我们已经确定了一个新的作用，甾醇生物合成途径，影响这一回收过程，可以显着提高EGFR靶向抑制剂的疗效。使用基于网络引导的siRNA筛选，SC 4 MOL（固醇C4-甲基氧化酶样）的沉默显著使肿瘤细胞对EGFR抑制剂敏感（Astsaturov，2010）。我们已经确定，SC 4 MOL和一个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ErbB 2和ErbB 3从质膜到溶酶体进行破坏的负调节剂。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，从而抑制EGFR信号在体外，在NSDHL条件性基因敲除小鼠，这将限制上皮癌变。我们的近期目标是验证一个新的代谢靶点，用于癌症治疗，涉及这些以前未探索的基因在远端甾醇生物合成途径。在强大的合作者团队的聚集下，我们提出了以下3个具体目标：目标1。研究固醇生物合成途径中基因对EGFR信号转导的调控机制。基于初步数据和互补的生物信息学分析，我们假设阻断SC 4 MOL和NSDHL导致EGFR转运改变，从而加速溶酶体中的EGFR降解。目标2.确定SC 4 MOL和EGFR在肿瘤异种移植物中的联合靶向价值。基于我们的初步体外数据，我们提出SC 4 MOL的shRNA沉默将增加肿瘤异种移植物对EGFR阻断的反应。目标3。研究固醇途径对EGFR信号传导和致癌物易感性的体内影响。我们推测上皮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。这一提议是重要的，因为它将提供关于固醇代谢如何调节必需的癌症受体（如EGFR）的信号传导活性的全新知识。我们认为，药理学抑制固醇途径的目标，如SC 4 MOL和NSDHL有潜力的癌症化疗和化学预防作为一个全新的代理类别。 公共卫生相关性：由医学博士Igor Astsaturov提交的NCI过渡职业发展奖（K22），博士提出研究调节EGFR信号传导的固醇代谢途径中的新的癌症相关靶点。该项目名为“靶向固醇基因SC 4 MOL和EGFR作为协同抗癌策略”，将提供有关固醇代谢阻断如何抑制活性和加速EGFR等基本癌症受体降解的全新知识。我们相信，固醇途径靶标SC 4 M01和相关NSDHL的药理学抑制具有为癌症化学疗法和化学预防提供基础的潜力，所述癌症化学疗法和化学预防具有完全新型的药剂类别。 个别评审员的书面评论和标准评分在下面的“评论”部分以基本上未经编辑的形式提供。请注意，这些评论和标准评分是在会议之前准备的，在审查会议上进行任何讨论之后可能没有进行修订。上文“讨论的简历和摘要”部分总结了委员会的最终意见。

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.