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eIF 4A 1治疗耐药乳腺癌干细胞样细胞 这个项目的首要目标是描述解旋酶活性的调节机制， eIF 4A 1控制多能性TF和ABC药物转运蛋白，以及如何利用这一点来克服药物 转移性TNBC中的耐药性。目前，尽管原发性乳腺癌的存活率有了显著提高， 在癌症患者中，90%的死亡率是由于侵袭性肿瘤的化学抗性导致转移。 新辅助血液疗法（NACT）是通过聚ADP-核糖聚合酶（PARP）治疗的主要方法。 抑制剂可与免疫疗法一起沿着使用。病理完全缓解（pCR）通常较低 在TNBC患者中。对NACT和靶向治疗的耐药主要是由于少数乳腺癌患者。 癌症干细胞样细胞（BCSC）或肿瘤起始细胞。BCSC具有内在的化学抗性， 可塑性和自我更新能力。它们的增殖和侵袭能力介导肿瘤发生、免疫调节和免疫调节。 逃避和转移。对化疗和免疫疗法的获得性耐药性也在治疗期间发展。 在这种治疗后，大量肿瘤细胞死亡，但BCSC存活，并构成微小残留病 （MRD）。存活的多能BCSC可以经历多谱系分化并重新填充整个细胞。 异质性肿瘤这导致肿瘤复发，其本质上更具侵袭性和高度转移性。 具有BCSC干性标志物（ALDH和CD 44）的高表达的肿瘤表现出最差的临床表现。 TNBC患者的结局。因此，存在对识别新靶标和战略性靶向的未满足的需求。 BCSC克服化疗耐药性，消除MRD并在转移性TNBC（mTNBC）中实现更好的pCR。 在这项研究中，我们建议找到的机制，解旋酶活性的eIF 4A 1调节 多能性，ABC转运蛋白，有助于耐药性。我们在目标1中提议确定 eIF 4A 1在体外调节多能性和ABC转运蛋白中的解旋酶活性。在aim 2中，我们将 确定eIF 4A 1的解旋酶活性在调节多能性和ABC转运蛋白中的作用， vivo.在aim 3中，我们建议将aim 1和aim 2中的发现转化为临床前PDX和CDX小鼠模型。这 将有助于开发在mTNBC中有效的新型组合疗法，并有望将其转化为人类 第一阶段试验。