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

靶向eIF4A1基因治疗耐药乳腺癌干细胞 这个项目的首要目标是描述解旋酶活性的调节机制。 以及如何利用eIF4A1控制多能性TF和ABC药物转运蛋白来克服药物 转移性TNBC的耐药性。目前，尽管初乳的存活率有了显著的改善 在癌症患者中，90%的死亡是由于侵袭性肿瘤的化疗耐药导致的转移。 新辅助血液治疗(Nact)是聚腺苷二磷酸核糖聚合酶(Parp)治疗的主要手段。 在免疫治疗的同时，也可以使用抑制剂。病理完全应答(PCR值)一般较低 在TNBC患者中。对NACT和靶向治疗的抵抗主要是由于乳房人口较少。 癌症干细胞(BCSCs)或肿瘤启动细胞。BCSCs本质上耐化疗，具有高 具有可塑性和自我更新能力。它们的增殖和侵袭能力介导了肿瘤的发生、免疫 逃避和转移。对化疗和免疫治疗的获得性耐药性也在治疗过程中产生。 在这种治疗之后，大部分肿瘤细胞死亡，但BCSC存活下来，构成最小的残留病 (MRD)。存活的多潜能BCSC可以经历多谱系分化并重新填充整个 异质性肿瘤。这会导致肿瘤复发，本质上更具侵袭性和高度转移性。 BCSC干细胞标记物(ALDH和CD44)高表达的肿瘤临床表现较差 TNBC患者的预后。因此，确定新的目标和战略目标的需求尚未得到满足。 BCSCs可以克服化疗耐药，消除MRD，并在转移性TNBC(MTNBC)中实现更好的PCR。 在本研究中，我们试图找出eIF4A1解旋酶活性调节的机制 多能性是导致化疗耐药的ABC转运蛋白。我们在目标1中建议确定 EIF4A1在体外调节多能性和ABC转运蛋白中的解旋酶活性。在AIM2中，我们将 确定eIF4A1的解旋酶活性在调节多能性和ABC转运蛋白中的作用 活着。在AIM 3中，我们建议将在AIM 1和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中有效的新的联合疗法，并有望将其转化为人类 第一阶段试验。

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.