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

• 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
• 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

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联合免疫治疗克服化疗耐药 长期目标是在三阴性中确定有效和新的靶向治疗的组合 乳腺癌(TNBC)克服临床化疗耐药。在这个项目中，我们建议以以下活动为目标 真核细胞翻译起始因子eIF4A1途径联合PD-L1免疫治疗三阴性 乳腺癌(TNBC)。目前，尽管ER+患者的存活率有了显著改善， Pr+和HER2+，TNBC患者病死率高。对转移的TNBC的治疗最初是 成功，但复发经常发生。这是由于化疗耐药的发展，最小的残留疾病。 (MRD)，复发的肿瘤具有高度侵袭性，转移或转移。乳腺癌 干细胞与乳腺癌耐药MRD的这种发展有关。 乳腺肿瘤细胞中的癌症干细胞通过乳腺之间的相互转化促进细胞可塑性 肿瘤干细胞(BCSCs)和大量肿瘤细胞(Non-BCSCs)。这种缓冲现象使TNBC很难 一种是获得对治疗的持久反应。我们最近发表了针对真核细胞翻译启动的研究报告 因子eIF4A1途径可有效诱导BCSCs死亡。EIF4A1是一种信使核糖核酸解旋酶 茎环结构存在于许多致癌mRNAs的5‘-前导区。这包括Survin，c- MYC、Cyclin D1、Cyclin D3、Hdm2、MCL1、ARF6、Mucin-1C、ROCK1和最近的STAT1已被卷入 EIF4A1的控制。STAT1增加了PD-L1基因的转录水平，因此 肿瘤细胞中PD-L1较多。PD-L1在肿瘤微环境中诱导T细胞无能。这就把我们带到了目标 EIF4A控制许多致癌的mRNAs翻译成包括PD-L1在内的癌蛋白。这提供了一种 将包含eIF4A1和c-myc的靶向治疗与PD-L1为基础的靶向治疗协同结合的机会 临床前小鼠模型的免疫治疗。我们在AIM 1中建议组合靶向eIF4A、c-myc和 免疫低下小鼠模型中PDX来源的异种移植中的Survivin。在AIM2中，我们将结合目标 EIF4A、c-myc联合抗PD-L1中和免疫治疗BALB/c小鼠 模型和毒性测试。这可能有助于形成靶向化疗的有效组合 和免疫疗法，以对抗TNBC的化疗耐药性。