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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：
10366263
负责人：
Dayanidhi Raman
金额：
$ 40.87万
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/10366263
关键词：
4T1 ABCB1 gene ABCC1 gene ABCG2 gene ATP-Binding Cassette Transporters Allografting Anthracycline Breast Cancer Cell Breast Cancer Patient CD44 gene 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 Immunotherapy In Vitro In complete remission MCL1 gene Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Nature Neoadjuvant Therapy Neoplasm Metastasis Oncogenic Outcome Pathologic Pharmaceutical Preparations Pharmacology Platinum Poly(ADP-ribose) Polymerases Polyribosomes Population Property Proteins Regulation Relapse Residual Neoplasm Resistance Role Structure Survival Rate Tetanus Helper Peptide Tissue Microarray Translating Treatment Failure Up-Regulation aldehyde dehydrogenases chemotherapy cyclin D3 efficacy evaluation feeding helicase immunoregulation in silico in vivo inhibitor insight knock-down malignant breast neoplasm mortality mouse model mutant neoplastic cell novel novel therapeutics patient derived xenograft model phase I trial pluripotency pre-clinical programs rho 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eIF4A1的耐药乳腺癌干细胞