Targeting of eIF4A along with immunotherapy to overcome chemoresistance

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Targeting of eIF4A along with immunotherapy to overcome chemoresistance The long-term objective is to identify combination of effective and novel targeted therapies in in triple-negative breast cancer (TNBC) to overcome clinical chemoresistance. In this project, we propose to target the activity of eukaryotic translation initiation factor eIF4A1 pathway along with PD-L1-based immunotherapy in triple-negative breast cancer (TNBC). Currently, despite significant improvements in the survival rates of patients that are ER+, PR+ and HER2+, mortality in TNBC patients is high. Therapeutic treatment for TNBC metastases is initially successful but relapse occurs often. This is due to development of chemoresistance, minimal residual disease (MRD) and the relapsed tumor is highly aggressive with metastasis or metastasis of the metastases. Breast cancer stemness has been implicated in such development of drug resistance MRD in breast cancer. Cancer stemness in breast tumor cells contributes to cellular plasticity with interconversion between breast cancer stem cells (BCSCs) and bulk tumor cells (non-BCSCs). This buffering phenomenon renders TNBC a difficult one to obtain a durable response to therapy. We published recently that targeting the eukaryotic translation initiation factor eIF4A1 pathway is effective in inducing cell death in BCSCs. eIF4A1 is an mRNA helicase that unwinds the stem-loop structures (SLS) present at the 5’-leader regions of many oncogenic mRNAs. This includes survivn, c- MYC, cyclin D1, cyclin D3, HDM2, MCL1, ARF6, Mucin-1C, ROCK1 and recently STAT1 has been implicated under the control of eIF4A1. STAT1 increases the transcript levels of programmed death ligand-1 (PD-L1) gene and hence more PD-L1 in tumor cells. PD-L1 induces T-cell anergy in the tumor microenvironment. This brings us to target eIF4A to control the translation of many oncogenic mRNAs into oncoproteins including PD-L1. This provides an opportunity to synergistically combine targeted therapy involving eIF4A1 and c-MYC with that of PD-L1 based immunotherapy in preclinical murine models. We propose in aim1 to combinatorially target eIF4A, c-MYC and survivin in PDX-derived xenografts in an immunocompromised murine model. In aim2, we will combine targeting of eIF4A, c-MYC with anti-PD-L1 neutralizing immunotherapy in a syngeneic, BALB/c immunocompetent murine model along with toxicity testing. This may facilitate in formulating effective combination of targeted chemotherapies and immunotherapy to combat chemoresistance in TNBC.