Translation Initiation Inhibitor for Cancer Therapy

用于癌症治疗的翻译起始抑制剂

• 批准号: 10412335
• 负责人: MOIRA SAUANE
• 金额: $ 14.16万
• 依托单位: HERBERT H. LEHMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412335
• 关键词: Adverse effects; Animal Model; Antineoplastic Agents; Apoptosis; Biochemical; Biological Assay; Biological Markers; Cause of Death; Cell Proliferation; Cessation of life; Clinical; Complex; Data; Development; Down-Regulation; Drug Kinetics; Ensure; Eukaryotic Initiation Factor-2; Genetically Engineered Mouse; Goals; Growth; Human; Immune checkpoint inhibitor; Immunology; In Vitro; Injections; Interleukin-24; Link; Lymphocyte Biology; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Modernization; Molecular; New York; Normal Cell; Nude Mice; Oncogenic; Phosphorylation; Physiological; Play; Proteins; Regulation; Role; Solid Neoplasm; T-Lymphocyte; Testing; Time; Toxic effect; Translation Initiation; Tumor Immunity; Tumor Suppression; Universities; Up-Regulation; Woman; Work; Xenograft procedure; activating transcription factor 4; age group; anti-cancer; anti-cancer therapeutic; anti-tumor immune response; anticancer activity; base; cancer cell; cancer therapy; cell growth regulation; efficacy study; experimental study; genetically modified cells; human cancer mouse model; immunogenicity; in vivo; inhibitor; medical schools; men; mouse model; mutant; neoplastic cell; primary endpoint; programmed cell death ligand 1; research clinical testing; restoration; therapeutic gene; tumor; tumor growth; tumor progression

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.

项目摘要 该项目的总体目标是扩展我们对细胞和分子机制的理解 链接翻译起始抑制作用对白介素-24触发的细胞凋亡和肿瘤抑制作用（IL-24）。 IL-24作为基于基因的治疗实体瘤的临床测试表明IL-24 是有效的，很安全。该提案与现代反癌治疗的当前观点一致 必须特异性靶标，抑制癌症的生长，对正常细胞的影响最小，并且有效抗 低毒性的癌症药物可以通过针对负责的基本机制来实现 癌症的起源，维持和/或进展。我们已经表明，IL-24抑制了通过 诱导真核起始因子2α（EIF2A）的磷酸化，三元络合物的消耗， ATF4表达和活性的上调，并在体外抑制EIF4F复合物。工作 该应用的假设是，通过 列鲁金24（IL-24）是一种翻译起始抑制剂，代表了癌症的新范式 治疗。我们已经对IL-24进行了药代动力学，毒性和体内功效研究 不仅其抗癌活性，而且IL-24在下调PD-L1的表达中，A 关键的抗肿瘤免疫因子。在此应用中，我们建议继续我们的努力来表征 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 癌症转化引发抑制介导的体内作用机理（特定目标1），2）确定 激活转录因子4（ATF4）在IL-24介导的翻译起始抑制和 凋亡（特定目标2）和3）首次研究PD-L1下调在抗 - IL-24的癌症及其作为免疫检查点抑制剂的潜在效用（特定目标3）。为此 拟议的研究，我们将与哈佛医学院的Bertal H. Aktas博士合作，专家 针对癌症治疗的翻译启动和纽约大学学校的Juan Lafaille博士 医学和免疫学专家。