Targeting Translation Dependence in Colorectal Cancer Progression

针对结直肠癌进展中的翻译依赖性

基本信息

批准号：
10533745
负责人：
QING-BAI SHE
金额：
$ 35.61万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533745
关键词：
Binding Proteins Biological Markers Biology Cancer Etiology Cell Line Cessation of life Clinical Colorectal Cancer Dependence Development Disease Down-Regulation EIF4EBP1 gene Environment Epigenetic Process FRAP1 gene Fostering Foundations Funding Genes Genetic Transcription Goals Immune Evasion Immunity Immunologic Surveillance Immunologist Immunotherapy Internal Ribosome Entry Site Knowledge Left Malignant Neoplasms Mediating Messenger RNA Molecular Monoclonal Antibodies Neoplasm Metastasis Oncogenic Oncologist Outcome Study Pathogenesis Pathologist Patients Phosphorylation Phosphorylation Inhibition Phosphotransferases Polyribosomes Positioning Attribute Process Production Property Protein Biosynthesis Proteins Public Health RNA RNA Helicase Reporting Research Resistance Role Signal Pathway Signal Transduction Snails T-Lymphocyte Testing Therapeutic Transact Translating Translation Initiation Translational Regulation Translations Treatment Efficacy Tumor Immunity Tumor-Infiltrating Lymphocytes United States Woman Work anti-PD-1 cancer cell clinically relevant colon cancer patients colorectal cancer progression colorectal cancer treatment effective therapy effectiveness evaluation experience genetic corepressor improved in vivo inhibitor inhibitor therapy innovation insight kinase inhibitor mRNA Translation mTOR Inhibitor men metastatic colorectal metastatic process mouse model novel novel strategies novel therapeutics patient derived xenograft model polysome profiling programmed cell death ligand 1 protein complex recruit response silvestrol targeted treatment therapeutic target treatment response tumor tumor growth

项目摘要

PROJECT SUMMARY Metastatic colorectal cancer (CRC) is an aggressive disease impacting about 50,000 deaths annually in the USA. Patients with metastatic CRC are predominantly unresponsive to existing therapies. The metastatic process is mediated in part by dysregulated translation of oncogenic mRNAs, leading to overproduction of their encoded proteins. Previous findings established dysregulation of cap-dependent mRNA translation downstream of mTOR at the level of 4E-BP1/eIF4E as a key to tumor formation and metastatic progression in CRC. While targeting mTOR is thought to be a promising strategy for CRC therapy, limited therapeutic efficacy of mTOR inhibitor drugs correlates largely with loss of the translation repressive function of 4E-BP1. More recent findings indicate that Snail acts as a strong repressor of 4E-BP1 transcription and cooperates with mTOR-mediated phosphorylation (inactivation) of 4E-BP1 to significantly increase eIF4E-initiated cap-dependent mRNA translation. These processes support tumor growth and decrease the efficacy of the mTOR kinase (ATP- competitive) inhibitors (mTORkis) in CRC therapy. Although mTORkis effectively inhibit phosphorylation of 4E- BP1 and restore its repressive effects on cap-dependent translation and tumor growth, treatment with mTORkis in CRC cells can promote the active translation and expression of the immunosuppressive protein PD-L1 via initiation at an internal ribosome entry site (IRES) in a cap-independent manner. In addition, the RNA helicase eIF4A is a key PD-L1 IRES binding protein that regulates its translation and expression. Importantly, elevated PD-L1 levels induced by mTORkis result in evasion of anti-CRC immunity. Further, targeted inhibition of PD-L1 can restore T-cell immunity and enhance the efficacy of mTORkis. Based on these findings, the central hypothesis of the proposed study is that CRC cells usurp the regulatory mechanisms underlying both cap- dependent translation through co-activation of Snail and mTOR and IRES-mediated translation of PD-L1 to escape immune surveillance in mTOR kinase-targeted therapy, thereby causing CRC resistance to mTORkis and promoting CRC progression. To test this hypothesis, the following specific aims are proposed: 1) to identify how Snail cooperates with mTOR in translational control of CRC progression and modulation of mTOR kinase- targeted therapy; 2) to determine the cap-independent mechanism of PD-L1 mRNA translation upon mTOR kinase inhibition; and 3) to define the in vivo utility of co-targeting PD-L1 and mTOR to enhance CRC therapy. The focus of this study is the innovative concept that both Snail and PD-L1 promote CRC progression by cooperating with mTOR to modulate therapeutic response to mTORkis through dysregulation of 4E-BP1- mediated translation initiation processes. This research will not only define the novel mechanistic roles of both Snail and PD-L1 in the modulation of mTOR/4E-BP1-mediated translational control of CRC progression and resistance to mTORkis, but also facilitate rational approaches for the development of new translatable therapeutic strategies for patients with advanced CRC.

项目概要转移性结直肠癌 (CRC) 是一种侵袭性疾病，每年导致约 50,000 人死亡美国。转移性结直肠癌患者对现有疗法大多没有反应。转移性的该过程部分是由致癌 mRNA 的翻译失调介导的，导致其过量产生编码的蛋白质。先前的研究结果证实了帽依赖性 mRNA 翻译下游的失调 4E-BP1/eIF4E 水平的 mTOR 是结直肠癌肿瘤形成和转移进展的关键。尽管靶向 mTOR 被认为是 CRC 治疗的一种有前途的策略，但 mTOR 的治疗效果有限抑制剂药物很大程度上与 4E-BP1 翻译抑制功能的丧失相关。更多最新发现表明 Snail 充当 4E-BP1 转录的强阻遏物，并与 mTOR 介导的合作 4E-BP1 磷酸化（失活）可显着增加 eIF4E 启动的帽依赖性 mRNA 翻译。这些过程支持肿瘤生长并降低 mTOR 激酶（ATP- CRC 治疗中的竞争性抑制剂 (mTORkis)。虽然 mTORkis 有效抑制 4E- 的磷酸化 BP1 并恢复其对帽依赖性翻译和肿瘤生长的抑制作用，用 mTORkis 治疗在CRC细胞中可以通过以下途径促进免疫抑制蛋白PD-L1的主动翻译和表达以不依赖帽的方式在内部核糖体进入位点（IRES）起始。此外，RNA 解旋酶 eIF4A 是一种关键的 PD-L1 IRES 结合蛋白，可调节其翻译和表达。重要的是，高 mTORkis 诱导的 PD-L1 水平导致抗 CRC 免疫的逃避。此外，靶向抑制PD-L1 可以恢复T细胞免疫力并增强mTORkis的功效。根据这些发现，中央拟议研究的假设是 CRC 细胞篡夺了两种帽的调节机制通过 Snail 和 mTOR 的共激活以及 IRES 介导的 PD-L1 翻译实现依赖性翻译 mTOR 激酶靶向治疗中逃避免疫监视，从而导致 CRC 对 mTORkis 耐药并促进CRC进展。为了检验这一假设，提出了以下具体目标：1）确定 Snail 如何与 mTOR 合作进行 CRC 进展的翻译控制和 mTOR 激酶的调节靶向治疗； 2) 确定 mTOR 上 PD-L1 mRNA 翻译的帽独立机制激酶抑制； 3) 确定联合靶向 PD-L1 和 mTOR 增强 CRC 治疗的体内效用。本研究的重点是 Snail 和 PD-L1 通过以下方式促进 CRC 进展的创新概念：与 mTOR 合作，通过 4E-BP1- 失调调节 mTORkis 的治疗反应介导的翻译起始过程。这项研究不仅将定义两者的新颖机制作用 Snail 和 PD-L1 在调节 mTOR/4E-BP1 介导的 CRC 进展的翻译控制中的作用对 mTORkis 的抵抗，同时也促进了开发新的可翻译药物的合理方法晚期结直肠癌患者的治疗策略。