Translation Initiation Inhibitor for Cancer Therapy

项目总结 这个项目的总体目标是扩大我们对细胞和分子机制的理解 翻译启动抑制与白介素24(IL-24)触发的细胞凋亡和肿瘤抑制有关。 IL-24作为以基因为基础的治疗实体瘤的临床试验表明 是有效且安全的。这一建议与当前的观点是一致的，即现代抗癌疗法 必须是靶向性的，在对正常细胞影响最小的情况下抑制肿瘤的生长，并且有效的抗肿瘤 低毒的抗癌药物可以通过靶向作用的基本机制来实现。 癌症的发生、维持和/或发展。我们已经证明，IL-24通过以下方式抑制翻译启动 诱导真核细胞起始因子2α(EIF2a)的磷酸化，耗尽三元复合体， 体外上调ATF4的表达和活性，抑制eIF4F复合体的表达。在工作中 这一应用的假设是通过以下方式恢复对翻译启动的生理抑制 白介素24(IL-24)是一种翻译起始抑制因子，代表了癌症治疗的新范式 心理治疗。我们已经对IL-24进行了药代动力学、毒性和体内疗效研究，建立了 不仅其抗癌活性，而且IL-24在翻译上下调PD-L1，a 关键的抗肿瘤免疫因子。在本应用程序中，我们建议继续努力将 IL-24作为翻译启动抑制因子的癌细胞特异性作用。具体来说，我们将1)检测IL-24抗- 肿瘤翻译启动抑制介导的体内作用机制(特异靶1)，2)决定 激活转录因子4在IL-24介导的翻译起始和抑制中的作用 细胞凋亡，(特定目的2)，3)首次研究PD-L1下调在抗肝癌中的作用 IL-24的癌症效应及其作为免疫检查点抑制物的潜在用途(特异性目标3)。为了这些 建议的研究，我们将与来自哈佛医学院的Bertal H.Aktas博士和 针对癌症治疗的翻译启动和纽约大学医学院的胡安·拉法耶博士 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.