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

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

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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以及免疫疗法以克服化学疗法长期目标是确定三阴性中有效和新颖的靶向疗法的组合乳腺癌（TNBC）以克服临床化学抗性。在这个项目中，我们建议针对真核翻译起始因子EIF4A1途径以及三阴性的基于PD-L1的免疫疗法乳腺癌（TNBC）。目前，尽管ER+的患者的存活率有显着提高，但 PR+和HER2+，TNBC患者的死亡率很高。 TNBC转移的治疗治疗最初是成功但退休经常发生。这是由于化学抗性，最小残留疾病的发展（MRD）和继电器肿瘤在转移的转移或转移方面具有高度侵略性。乳腺癌在这种抗药性MRD中，乳腺癌中的耐药性MRD已被浸渍。乳腺肿瘤细胞中的癌症有助于细胞可塑性，乳房之间的相互转换癌干细胞（BCSC）和大量肿瘤细胞（非BCSC）。这种缓冲现象使TNBC困难一个获得对治疗的持久反应。我们最近发表了针对真核翻译启动的因子EIF4A1途径在BCSC中有效诱导细胞死亡。 EIF4A1是一个mRNA解旋酶，可以放松在许多致癌mRNA的5'-Leader区域存在的茎环结构（SLS）。这包括survivn，c- MYC，Cyclin D1，Cyclin D3，HDM2，Mcl1，Arf6，Mucin-1c，Rock1和最近的STAT1在 EIF4A1的控制。 STAT1增加了编程死亡配体1（PD-L1）基因的转录水平，因此肿瘤细胞中更多的PD-L1。 PD-L1在肿瘤微环境中诱导T细胞反感。这使我们成为目标 EIF4A控制许多致癌性mRNA转化为包括PD-L1在内的癌蛋白。这提供了有机会将涉及EIF4A1和C-MYC与PD-L1的靶向疗法协同相结合临床前鼠模型中的免疫疗法。我们在AIM1中提出了针对EIF4A，C-MYC和在免疫功能低下的鼠模型中，PDX衍生的Xenographictics中的Survivin。在AIM2中，我们将结合目标 EIF4A，C-MYC，具有抗PD-L1的抗PD-L1中和免疫疗法模型以及毒性测试。这可能有助于制定目标化学疗法的有效组合和免疫疗法以对抗TNBC的化学抗性。