Targeting eIF4A1 in drug-resistant breast cancer stem-like cells

靶向耐药乳腺癌干细胞中的 eIF4A1

• 批准号: 10680365
• 负责人: Dayanidhi Raman
• 金额: $ 40.06万
• 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: 2022-08-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680365
• 关键词: 4T1; ABCB1 gene; ABCC1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Adjuvant Chemotherapy; Allografting; Anthracycline; Apoptosis; Breast Cancer Cell; Breast Cancer Patient; CD44 gene; Cell Survival; Cells; Chemoresistance; Clinic; Clinical; Combined Modality Therapy; Cyclin D1; Data; Disease; Distant Metastasis; Drug Targeting; Drug resistance; Eukaryotic Initiation Factors; Fractionation; Goals; Human; Immune Evasion; Immunologic Deficiency Syndromes; Immunotherapy; In Vitro; In complete remission; Invaded; MCL1 gene; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Mus; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Pharmaceutical Preparations; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Polyribosomes; Population; Proliferating; Property; Protein Biosynthesis; Proteins; Regulation; Relapse; Residual Neoplasm; Resistance; Rho-associated kinase; Role; Structure; Survival Rate; Tetanus Helper Peptide; Tissue Microarray; Translating; Treatment Failure; Up-Regulation; aldehyde dehydrogenases; cyclin D3; efficacy evaluation; helicase; immunoregulation; improved; in silico; in vivo; insight; knock-down; malignant breast neoplasm; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; pharmacologic; phase I trial; pluripotency; pre-clinical; programs; self-renewal; stem-like cell; stemness; survivin; targeted treatment; taxane; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor initiation; tumorigenesis

Targeting eIF4A1 in drug-resistant breast cancer stem-like cells The overarching goal of this project is to delineate the regulatory mechanisms by which the helicase activity of eIF4A1 controls pluripotency TFs and ABC drug transporters and how this can be exploited to overcome drug resistance in metastatic TNBC. Currently, despite significant improvements in the survival rates of primary breast cancer patients, 90% of the mortality is due to chemoresistance from aggressive tumors leading to metastasis. Neoadjuvant hemotherapy (NACT) is the mainstay of treatment though poly ADP-ribose polymerase (PARP) inhibitors are available along with immunotherapy. The pathological complete response (pCR) is generally low in TNBC patients. Resistance to NACT and also to targeted therapy is mainly due to a small population of breast cancer stem-like cells (BCSCs) or tumor-initiating cells. BCSCs are intrinsically chemoresistant with high plasticity and self-renewal capability. Their proliferative and invasive capacity mediates tumorigenesis, immune evasion and metastasis. Acquired resistance to chemo- and immunotherapy also develops during treatment. Following such therapy, the bulk tumor cells die but BCSCs survive and constitute the minimal residual disease (MRD). The surviving pluripotent BCSCs can undergo multi-lineage differentiation and repopulate the entire heterogeneous tumor. This leads to tumor relapse which are more aggressive and highly metastatic in nature. Tumors with high expression of BCSC stemness markers (ALDH and CD44) demonstrate worst clinical outcomes in TNBC patients. Thus, there is an unmet need for identifying novel targets and strategically target BCSCs to overcome chemoresistance, eliminate MRD and achieve better pCR in metastatic TNBC (mTNBC). In this study, we propose to find the mechanisms by which the helicase activity of eIF4A1 regulates pluripotency, ABC transporters that contribute to chemoresistance. We propose in aim 1 to determine the role of the helicase activity of eIF4A1 in the regulation of pluripotency and ABC transporters in vitro. In aim2, we will determine the role of the helicase activity of eIF4A1 in the regulation of pluripotency and ABC transporters in vivo. In aim3 we propose to translate the findings in aim1 and 2 to preclinical PDX and CDX murine models. This will facilitate in developing novel combination therapies effective in mTNBC and hopefully translate it into human phase I trial.

靶向耐药性乳腺癌干细胞中的EIF4A1 该项目的总体目标是描述解旋酶活性的调节机制 EIF4A1的控制多能TFS和ABC药物转运蛋白以及如何利用它来克服药物 转移性TNBC的抗性。目前，尽管原发性乳房的存活率显着提高 癌症患者，死亡率的90％是由于导致转移的侵袭性肿瘤化学抗性。 新辅助血液疗法（NACT）是治疗的主要ADP-核糖聚合酶（PARP） 抑制剂可与免疫疗法一起使用。病理完全反应（PCR）通常很低 在TNBC患者中。对NACT的抵抗力以及对靶向疗法的耐药性主要是由于乳房的少数 癌症干细胞（BCSC）或肿瘤发射细胞。 BCSC本质上是化学抗性的，高 可塑性和自我更新能力。它们的增殖和侵入性能力介导肿瘤发生，免疫 逃避和转移。在治疗期间，获得的对化学和免疫疗法的耐药性也会发展出来。 这种疗法后，大量肿瘤细胞死亡，但BCSC生存并构成最小残留疾病 （MRD）。尚存的多能BCSC可以进行多条不通的分化，并重新填充整个 异质肿瘤。这导致肿瘤复发，本质上更具侵略性和高度转移性。 BCSC干性标记（ALDH和CD44）表达高表达的肿瘤表现出最坏的临床 TNBC患者的结果。因此，没有满足的需求来识别新颖的目标并在战略上靶向 BCSC克服化学抗性，消除MRD并在转移性TNBC（MTNBC）中获得更好的PCR。 在这项研究中，我们建议找到EIF4A1的解旋酶活性调节的机制 多能力，ABC转运蛋白有助于化学抗性。我们建议在AIM 1中确定 EIF4A1在体外调节多能和ABC转运蛋白中的解旋酶活性。在AIM2中，我们将 确定EIF4A1的解旋酶活性在多能性和ABC转运蛋白调节中的作用 体内。在AIM3中，我们建议将AIM1和2中的发现转换为临床前PDX和CDX鼠模型。这 将有助于开发有效的MTNBC的新型组合疗法，并希望将其转化为人类 第一阶段试验。