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

靶向耐药乳腺癌干细胞中的 eIF4A1

基本信息

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
项目类别：
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

项目摘要

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 控制多能性 TF 和 ABC 药物转运蛋白以及如何利用它来克服药物转移性 TNBC 的耐药性。目前，尽管原发性乳房的存活率显着提高癌症患者中，90%的死亡率是由于侵袭性肿瘤的化疗耐药导致转移所致。新辅助血液疗法 (NACT) 是通过聚 ADP 核糖聚合酶 (PARP) 进行治疗的主要方法抑制剂可与免疫疗法一起使用。病理完全缓解（pCR）普遍较低 TNBC 患者。对 NACT 和靶向治疗的耐药性主要是由于少数乳腺患者癌症干细胞样细胞（BCSC）或肿瘤起始细胞。 BCSC 本质上具有高耐药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、免疫逃避和转移。在治疗过程中也会产生对化疗和免疫治疗的获得性耐药。经过这种治疗后，大部分肿瘤细胞死亡，但 BCSC 存活并构成微小残留病（MRD）。幸存的多能 BCSC 可以进行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。 BCSC 干性标志物（ALDH 和 CD44）高表达的肿瘤表现出最差的临床表现 TNBC 患者的结果。因此，确定新目标和战略目标的需求尚未得到满足 BCSC 在转移性 TNBC (mTNBC) 中克服化疗耐药性、消除 MRD 并实现更好的 pCR。在本研究中，我们打算寻找 eIF4A1 解旋酶活性调节的机制多能性，ABC转运蛋白有助于化学抗性。我们在目标 1 中建议确定 eIF4A1 解旋酶活性在体外调节多能性和 ABC 转运蛋白中的作用。在目标2中，我们将确定 eIF4A1 解旋酶活性在调节多能性和 ABC 转运蛋白中的作用体内。在目标 3 中，我们建议将目标 1 和 2 中的发现转化为临床前 PDX 和 CDX 小鼠模型。这将促进开发有效治疗 mTNBC 的新型联合疗法，并有望将其转化为人类第一阶段试验。