Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada.
Cancer Cell. 2011 Oct 18;20(4):443-56. doi: 10.1016/j.ccr.2011.09.005.
To identify therapeutic opportunities for oncolytic viral therapy, we conducted genome-wide RNAi screens to search for host factors that modulate rhabdoviral oncolysis. Our screens uncovered the endoplasmic reticulum (ER) stress response pathways as important modulators of rhabdovirus-mediated cytotoxicity. Further investigation revealed an unconventional mechanism whereby ER stress response inhibition preconditioned cancer cells, which sensitized them to caspase-2-dependent apoptosis induced by a subsequent rhabdovirus infection. Importantly, this mechanism was tumor cell specific, selectively increasing potency of the oncolytic virus by up to 10,000-fold. In vivo studies using a small molecule inhibitor of IRE1α showed dramatically improved oncolytic efficacy in resistant tumor models. Our study demonstrates proof of concept for using functional genomics to improve biotherapeutic agents for cancer.
为了寻找溶瘤病毒治疗的机会，我们进行了全基因组 RNAi 筛选，以寻找调节杆状病毒溶瘤作用的宿主因素。我们的筛选发现，内质网（ER）应激反应途径是调节杆状病毒介导的细胞毒性的重要调节剂。进一步的研究揭示了一种非传统的机制，即 ER 应激反应抑制预先处理癌细胞，使它们对随后的杆状病毒感染诱导的 caspase-2 依赖性细胞凋亡敏感。重要的是，这种机制是肿瘤细胞特异性的，通过将溶瘤病毒的效力选择性提高多达 10000 倍。使用 IRE1α 的小分子抑制剂的体内研究表明，在耐药肿瘤模型中，溶瘤病毒的治疗效果显著改善。我们的研究证明了使用功能基因组学来改善癌症的生物治疗药物的概念验证。
