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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）是一种侵袭性疾病，在美国每年影响约50，000例死亡。 USA.转移性CRC患者主要对现有疗法无反应。转移性这一过程部分是由致癌基因mRNAs的翻译失调介导的，导致它们的过度产生。编码蛋白质。先前的研究结果建立了帽依赖性mRNA翻译下游的失调 mTOR在4 E-BP 1/eIF 4 E水平的表达是CRC肿瘤形成和转移进展的关键。而靶向mTOR被认为是CRC治疗的有前景的策略，mTOR的治疗效果有限，抑制剂药物与4 E-BP 1的翻译抑制功能的丧失在很大程度上相关。最近的发现表明Snail作为4 E-BP 1转录强阻遏物，与mTOR介导的 4 E-BP 1的磷酸化（失活）以显著增加eIF 4 E起始的帽依赖性mRNA 翻译.这些过程支持肿瘤生长并降低mTOR激酶（ATP-1）的功效。竞争性）抑制剂（mTORkis）在CRC治疗中的应用。虽然mTORkis有效抑制4 E- BP 1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：在内部核糖体进入位点（IRES）以帽非依赖性方式起始。此外，RNA解旋酶 eIF 4A是调节其翻译和表达的关键PD-L1 IRES结合蛋白。重要的是， mTORkis诱导的PD-L1水平导致抗CRC免疫逃避。此外，靶向抑制PD-L1 可恢复T细胞免疫力，增强mTORkis的疗效。根据这些发现，中央这项研究的假设是，CRC细胞篡夺了两种帽- 通过Snail和mTOR的共激活的依赖性翻译和IRES介导的PD-L1翻译，在mTOR激酶靶向治疗中逃避免疫监视，从而导致CRC对mTOR激酶耐药促进CRC进展。为了验证这一假设，提出了以下具体目标：1）识别 Snail如何与mTOR在CRC进展的翻译控制和mTOR激酶的调节中合作- 靶向治疗; 2）确定PD-L1 mRNA在mTOR上翻译的帽非依赖性机制激酶抑制;和3）确定共靶向PD-L1和mTOR增强CRC治疗的体内效用。本研究的重点是创新概念，即Snail和PD-L1均通过以下方式促进CRC进展：与mTOR协同作用，通过4 E-BP 1 - 1的失调调节对mTOR kis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制作用， Snail和PD-L1调节mTOR/4 E-BP 1介导的CRC进展的翻译控制，对mTORkis的抗性，但也有利于合理的方法来开发新的可翻译晚期CRC患者的治疗策略。