Translation Initiation Inhibitor for Cancer Therapy

项目摘要 该项目的总体目标是扩大我们对细胞和分子机制的理解， 将翻译起始抑制与白细胞介素-24（IL-24）引发的细胞凋亡和肿瘤抑制联系起来。 IL-24作为用于治疗实体瘤的基于基因的治疗剂的临床测试证明IL-24 有效且安全。这一建议与目前认为现代抗癌疗法 必须是靶向特异性的，抑制癌症的生长，对正常细胞的影响最小，并且有效的抗- 低毒性的抗癌剂可以通过靶向引起肿瘤的基本机制来实现。 癌症的发生、维持和/或进展。我们已经证明，IL-24通过以下方式抑制翻译起始： 诱导真核起始因子2 α（eIF 2a）的磷酸化，消耗三元复合物， 在体外上调ATF 4的表达和活性，并抑制eIF 4F复合物。工作 本申请假设是通过以下方式恢复对翻译起始的生理抑制 白细胞介素24（IL-24）是一种翻译起始抑制剂，代表了癌症的新范式 疗法我们对IL-24进行了药代动力学、毒性和体内功效研究， IL-24不仅具有抗癌活性，而且抑制性下调PD-L1的表达， 关键的抗肿瘤免疫因子。在本申请中，我们提出继续努力表征 IL-24作为翻译起始抑制剂的癌细胞特异性作用。具体而言，我们将1）测试IL-24抗- 癌症翻译起始抑制介导的体内作用机制（特异性目的1），2）确定 转录激活因子4（ATF 4）在IL-24介导的翻译起始抑制中的作用， 凋亡，（特异性目的2），和3）首次研究PD-L1下调在抗凋亡中的作用， IL-24的癌症效应及其作为免疫检查点抑制剂的潜在效用（具体目标3）。为这些 建议的研究，我们将与博士Bertal H.来自哈佛医学院的阿克塔斯是 癌症治疗的靶向翻译起始和来自纽约大学医学院的Juan Lafaille博士 医学和免疫学专家。

PROJECT SUMMARY The overall goal of this project is to expand our understanding of the cellular and molecular mechanisms that link translation initiation inhibition to apoptosis and tumor suppression triggered by Interleukin-24 (IL-24). Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. This proposal is consistent with the current view that modern anti-cancer therapy must be target-specific, inhibit the growth of cancer with minimal effect on normal cells, and that effective anti- cancer agents of low toxicity can be achieved by targeting the fundamental mechanisms responsible for the genesis, maintenance, and/or progression of cancer. We have shown that IL-24 inhibits translation initiation by inducing phosphorylation of eukaryotic initiation factor 2 alpha (eIF2a), depletion of the ternary complex, upregulation of expression and activity of ATF4, and inhibition of eIF4F complex in vitro. The working hypothesis of this application is that restoration of physiological restrains on translation initiation by Interleukin 24 (IL-24), an inhibitor of translation initiation, represents a new paradigm in cancer therapy. We have conducted pharmacokinetic, toxicity, and in vivo efficacy studies on IL-24, which established not only its anti-cancer activity, but also that IL-24 translationally down-regulates the expression of PD-L1, a critical anti-tumor immunity factor. In this application we propose to continue our efforts to characterize the cancer cell-specific actions of IL-24 as an inhibitor of translation initiation. Specifically, we will 1) test IL-24 anti- cancer translation initiation inhibition-mediated mechanism of action in vivo (Specific Aim 1), 2) determine the role of activating transcription factor 4 (ATF4) on IL-24-mediated inhibition of translation initiation and apoptosis, (Specific Aim 2), and 3) investigate for the first time the role of PD-L1 down-regulation in the anti- cancer effect of IL-24 and its potential utility as an immune checkpoint inhibitor (Specific Aim 3). For these proposed studies, we will collaborate with Dr. Bertal H. Aktas, from Harvard Medical School, and expert on targeting translation initiation for cancer therapy and Dr. Juan Lafaille, from New York University School of Medicine, and Immunology expert.