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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：
10544331
负责人：
Dayanidhi Raman
金额：
$ 17.7万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544331
关键词：
4T1 ABCB1 gene ABCC1 gene ABCG2 gene Ablation Adjuvant Chemotherapy Allografting Antibodies Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast cancer metastasis Buffers Cartoons Cell Death Induction 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 Immunologic Deficiency Syndromes Immunotherapy In Vitro Inbred BALB C Mice Invaded 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 Population Proliferating Property Protein Translation Pathway Publishing ROCK1 gene Relapse Research Residual Neoplasm Resistance Resistance profile Rho-associated kinase Risk STAT1 gene Structure Survival Rate T cell anergy Therapeutic Toxicity Tests Transcript Translations Treatment Failure Up-Regulation Xenograft procedure anti-cancer c-myc Genes cancer stem cell checkpoint inhibition chemotherapy clinical efficacy combat combinatorial cyclin D3 cytotoxic drug resistance development helicase immune checkpoint immunoregulation improved in vivo inhibitor malignant breast neoplasm mortality mouse model neoplastic cell new therapeutic target patient derived xenograft model pharmacologic phase I trial pluripotency pre-clinical programmed cell death ligand 1 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 eIF4A 并结合免疫疗法克服化疗耐药性长期目标是确定三阴性患者中有效和新颖的靶向疗法的组合乳腺癌（TNBC）克服临床化疗耐药性。在这个项目中，我们建议以以下活动为目标：真核翻译起始因子 eIF4A1 通路与基于 PD-L1 的三阴性免疫治疗乳腺癌（TNBC）。目前，尽管 ER+ 患者的生存率显着提高， PR+和HER2+，TNBC患者死亡率较高。 TNBC 转移的治疗最初是成功但经常复发。这是由于化学耐药性、微小残留病的发展 (MRD)并且复发的肿瘤具有高度侵袭性并伴有转移或转移灶的转移。乳腺癌干性与乳腺癌耐药性 MRD 的发展有关。乳腺肿瘤细胞中的癌症干细胞有助于细胞可塑性与乳腺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 TNBC 变得困难一种获得持久治疗反应的方法。我们最近发表了针对真核翻译起始的研究因子 eIF4A1 通路可有效诱导 BCSC 细胞死亡。 eIF4A1 是一种 mRNA 解旋酶，可解旋茎环结构 (SLS) 存在于许多致癌 mRNA 的 5’-前导区域。这包括生存，c- MYC、细胞周期蛋白 D1、细胞周期蛋白 D3、HDM2、MCL1、ARF6、Mucin-1C、ROCK1 和最近的 STAT1 已被涉及 eIF4A1 的控制。 STAT1 增加程序性死亡配体-1 (PD-L1) 基因的转录水平，因此肿瘤细胞中存在更多的 PD-L1。 PD-L1 在肿瘤微环境中诱导 T 细胞无反应。这使我们达到目标 eIF4A 控制许多致癌 mRNA 翻译成癌蛋白，包括 PD-L1。这提供了一个将涉及 eIF4A1 和 c-MYC 的靶向治疗与基于 PD-L1 的靶向治疗协同结合的机会临床前小鼠模型中的免疫治疗。我们在 goal1 中建议组合靶向 eIF4A、c-MYC 和免疫功能低下的小鼠模型中 PDX 衍生的异种移植物中的生存素。在 Target2 中，我们将结合以下目标在同基因 BALB/c 免疫活性小鼠中使用 eIF4A、c-MYC 和抗 PD-L1 中和免疫疗法模型以及毒性测试。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 的化疗耐药性。