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，配体诱导的活化受体内化及其在溶酶体中降解的分选是EGFR信号传导的限制机制。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来促进其生长和存活。我们已经确定了甾醇生物合成途径在影响这一循环过程中的新作用，这可以显著提高egfr靶向抑制剂的功效。使用基于sirna的网络引导筛选，沉默SC4MOL（甾醇c4 -甲基氧化酶样）可显著提高肿瘤细胞对EGFR抑制剂的敏感性（Astsaturov, 2010）。我们已经确定SC4MOL和一个功能连接的伴侣蛋白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，代谢阻断甾醇生物合成途径将加速受体降解，从而抑制体外EGFR信号传导；在NSDHL条件敲除小鼠中，这将限制上皮癌变。我们的直接目标是验证癌症治疗的新代谢靶点，涉及远端固醇生物合成途径中这些先前未被探索的基因。在强大的合作团队的支持下，我们提出以下3个具体目标：探讨甾醇生物合成途径中基因调控EGFR信号通路的机制。根据初步数据和补充的生物信息学分析，我们假设阻断SC4MOL和NSDHL会导致EGFR转运改变，从而加速溶酶体中EGFR的降解。目标2。确定SC4MOL和EGFR联合靶向在异种肿瘤移植中的价值。基于我们初步的体外实验数据，我们提出shRNA沉默SC4MOL会增加肿瘤异种移植物对EGFR阻断的反应。目标3。研究体内甾醇通路对EGFR信号传导和致癌物易感性的影响。我们假设上皮细胞NSDHL缺乏的egfr拮抗作用将限制h - ras依赖性或非依赖性癌变。这一建议意义重大，因为它将从根本上提供关于固醇代谢如何调节基本癌症受体（如EGFR）的信号活性的新知识。我们认为，作为一类全新的药物，抑制甾醇途径靶点如SC4MOL和NSDHL具有癌症化疗和化学预防的潜力。

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.