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Targeting of eIF4A along with immunotherapy to overcome chemoresistance

靶向 eIF4A 并结合免疫疗法克服化疗耐药性

基本信息

批准号：
10357016
负责人：
Dayanidhi Raman
金额：
$ 21.67万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357016
关键词：
4T1 ABCB1 gene ABCC1 gene ABCG2 gene Ablation Allografting Antibodies Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast cancer metastasis Buffers Cartoons Cell Death Chemoresistance Clinical Clinical Management Combined Modality Therapy Cyclin D1 Data Development Diagnosis Distant Metastasis Drug resistance ERBB2 gene Emergency Department patient Estrogen receptor positive Eukaryotic Initiation Factors FDA approved Genes Genetic Genetic Transcription Human Immune Evasion Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunotherapy In Vitro Inbred BALB C Mice Lead MCL1 gene MDM2 gene Malignant Neoplasms Measures Mediating Messenger RNA Mucins Mus Neoadjuvant Therapy Neoplasm Metastasis Oncogenic Oncoproteins Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Pharmacology Population Property Protein Translation Pathway Publishing ROCK1 gene Relapse Research Residual Neoplasm Resistance Resistance profile Risk STAT1 gene Structure Survival Rate T cell anergy Therapeutic Toxicity Tests Transcript Translations Treatment Failure Up-Regulation Xenograft procedure anti-cancer base c-myc Genes cancer stem cell checkpoint inhibition chemotherapy clinical efficacy combat combinatorial cyclin D3 cytotoxic drug development helicase immune checkpoint immunoregulation improved in vivo inhibitor malignant breast neoplasm mortality mouse model neoplastic cell new therapeutic target patient derived xenograft model phase I trial pluripotency pre-clinical programmed cell death ligand 1 rho rocaglamide self-renewal small molecule inhibitor standard of care stem stem-like cell stemness survivin targeted treatment transcription factor translational impact treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Targeting of eIF4A along with immunotherapy to overcome chemoresistance The long-term objective is to identify combination of effective and novel targeted therapies in in triple-negative breast cancer (TNBC) to overcome clinical chemoresistance. In this project, we propose to target the activity of eukaryotic translation initiation factor eIF4A1 pathway along with PD-L1-based immunotherapy in triple-negative breast cancer (TNBC). Currently, despite significant improvements in the survival rates of patients that are ER+, PR+ and HER2+, mortality in TNBC patients is high. Therapeutic treatment for TNBC metastases is initially successful but relapse occurs often. This is due to development of chemoresistance, minimal residual disease (MRD) and the relapsed tumor is highly aggressive with metastasis or metastasis of the metastases. Breast cancer stemness has been implicated in such development of drug resistance MRD in breast cancer. Cancer stemness in breast tumor cells contributes to cellular plasticity with interconversion between breast cancer stem cells (BCSCs) and bulk tumor cells (non-BCSCs). This buffering phenomenon renders TNBC a difficult one to obtain a durable response to therapy. We published recently that targeting the eukaryotic translation initiation factor eIF4A1 pathway is effective in inducing cell death in BCSCs. eIF4A1 is an mRNA helicase that unwinds the stem-loop structures (SLS) present at the 5’-leader regions of many oncogenic mRNAs. This includes survivn, c- MYC, cyclin D1, cyclin D3, HDM2, MCL1, ARF6, Mucin-1C, ROCK1 and recently STAT1 has been implicated under the control of eIF4A1. STAT1 increases the transcript levels of programmed death ligand-1 (PD-L1) gene and hence more PD-L1 in tumor cells. PD-L1 induces T-cell anergy in the tumor microenvironment. This brings us to target eIF4A to control the translation of many oncogenic mRNAs into oncoproteins including PD-L1. This provides an opportunity to synergistically combine targeted therapy involving eIF4A1 and c-MYC with that of PD-L1 based immunotherapy in preclinical murine models. We propose in aim1 to combinatorially target eIF4A, c-MYC and survivin in PDX-derived xenografts in an immunocompromised murine model. In aim2, we will combine targeting of eIF4A, c-MYC with anti-PD-L1 neutralizing immunotherapy in a syngeneic, BALB/c immunocompetent murine model along with toxicity testing. This may facilitate in formulating effective combination of targeted chemotherapies and immunotherapy to combat chemoresistance in TNBC.

靶向eIF 4A沿着免疫治疗以克服化疗耐药性长期目标是确定有效的和新的靶向治疗在三阴性的组合乳腺癌（TNBC），以克服临床化疗耐药性。在这个项目中，我们建议将以下活动作为目标：真核生物翻译起始因子eIF 4A 1通路沿着基于PD-L1的免疫治疗在三阴性乳腺癌（TNBC）。目前，尽管ER+患者的生存率有了显著提高， PR+和HER 2+，TNBC患者的死亡率很高。TNBC转移的治疗性治疗最初是成功，但经常复发。这是由于化疗耐药性的发展，微小残留病 (MRD)并且复发的肿瘤具有高度侵袭性，伴有转移或转移灶的转移。乳腺癌干性与乳腺癌中耐药性MRD的发展有关。乳腺癌细胞的癌干性有助于细胞可塑性与乳腺癌之间的相互转化癌症干细胞（BCSC）和大量肿瘤细胞（非BCSC）。这种缓冲现象使得TNBC难以一个是对治疗有持久的反应我们最近发表了针对真核翻译起始的研究因子eIF 4A 1通路在BCSC中有效诱导细胞死亡。eIF 4A 1是一种mRNA解旋酶，茎环结构（SLS）存在于许多致癌mRNA的5 '-前导区。这包括生存，C- MYC、细胞周期蛋白D1、细胞周期蛋白D3、HDM 2、MCL 1、ARF 6、粘蛋白-1C、ROCK 1和最近的STAT 1与控制eIF 4A 1。STAT 1增加程序性死亡配体-1（PD-L1）基因的转录水平，更多的PD-L1在肿瘤细胞中。PD-L1在肿瘤微环境中诱导T细胞无反应性。这就把我们带到了目标 eIF 4A控制许多致癌mRNA翻译成癌蛋白，包括PD-L1。这提供了一将涉及eIF 4A 1和c-MYC的联合收割机靶向治疗与基于PD-L1的靶向治疗协同组合的机会临床前小鼠模型中的免疫治疗。我们在aim 1中提出组合靶向eIF 4A、c-MYC和免疫受损小鼠模型中PDX衍生的异种移植物中的存活素。在aim 2中，我们将把联合收割机的目标定位 eIF 4A、c-MYC联合抗PD-L1中和免疫治疗在同基因BALB/c免疫活性鼠中的应用模型沿着毒性测试。这可能有助于制定有效的靶向化疗组合和免疫疗法来对抗TNBC中的化学抗性。