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.

项目摘要转移性结直肠癌（CRC）是一种侵略性疾病，每年影响约50,000人死亡美国。转移性CRC的患者主要对现有疗法无反应。转移性过程的部分原因是致癌mRNA的翻译失调，导致其生产过多编码的蛋白质。以前的发现确定了下游帽依赖性mRNA翻译的失调 MTOR在4E-BP1/EIF4E水平上是CRC中肿瘤形成和转移性进展的关键。尽管靶向MTOR被认为是CRC治疗的有前途的策略，MTOR的治疗功效有限抑制剂药物在很大程度上与4E-BP1翻译抑制功能的丧失相关。最新的发现表明蜗牛充当4e-bp1转录的强阻遏物，并与mtor介导的合作 4E-BP1的磷酸化（灭活）以显着增加EIF4E引起的帽依赖性mRNA 翻译。这些过程支持肿瘤生长并降低MTOR激酶的功效（ATP- CRC治疗中的竞争性抑制剂（mtorkis）。尽管mtorkis有效抑制了4E-的磷酸化 BP1并恢复其对依赖帽依赖性翻译和肿瘤生长的抑制作用，用mtorkis处理在CRC细胞中可以促进免疫抑制蛋白PD-L1通过独立于胶囊的方式在内部核糖体进入位点（IRES）的启动。另外，RNA解旋酶 EIF4A是调节其翻译和表达的关键PD-L1 IRES结合蛋白。重要的是，高架 MTorkis诱导的PD-L1水平导致逃避抗CRC免疫。此外，针对PD-L1的靶向抑制可以恢复T细胞免疫力并增强mtorkis的功效。基于这些发现，中央拟议的研究的假设是，CRC细胞篡夺了两者cap-的调节机制通过共同激活蜗牛和MTOR和IRES介导的PD-L1的翻译来转换 MTOR激酶靶向疗法中的逃避免疫监视，从而引起CRC抗性mtorkis 并促进CRC的进展。为了检验该假设，提出了以下特定目的：1）确定蜗牛如何与MTOR合作在CRC进展的转化控制和MTOR激酶的调节中靶向治疗； 2）确定MTOR时PD-L1 mRNA翻译的帽无关机制激酶抑制； 3）定义共同靶向PD-L1和MTOR的体内效用以增强CRC治疗。这项研究的重点是创新概念，蜗牛和PD-L1均通过与MTOR合作通过4E-BP1-的失调来调节对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机械作用 MTOR/4E-BP1介导的CRC进展的转化控制和PD-L1的蜗牛和PD-L1 抵抗Mtorkis，但也有助于开发新的可翻译的理性方法晚期CRC患者的治疗策略。