Saturday, November 23, 2024
11/23/2024
Targeting of eIF4A1 in drug-resistant breast cancer stem-like cells The overarching goal of this supplement project to the parent R01 grant is to obtain preliminary data that points to disproportionate facilitation of cancer stemness by mRNA helicase eIF4A1 in African American (AA) than European White (EW) triple-negative breast cancer (TNBC) patients. Currently, there is more than 90% of mortality in TNBC due to metastasis. This is due to chemoresistance and recurrence emanating from cancer stemness. Neoadjuvant hemotherapy (NACT) is the mainstay of treatment for TNBC though FDA-approved poly ADP-ribose polymerase (PARP) inhibitors are available along with immunotherapy (Atezolizumab). Despite the availability of these therapeutic modalities, the observed pathological complete response (pCR) is lower in AA- TNBC than EW-TNBC patients. Development of resistance to NACT and targeted therapies is due to the presence of a small population of breast cancer stem-like cells (BCSCs) or tumor-initiating cells in the tumor. BCSCs are pro-tumorigenic in nature as they are capable of self-renewal. The high plasticity of BCSCs allows them to transdifferentiate into bulk tumor and stromal cells. More importantly. BCSCs are intrinsically chemoresistant but can acquire resistance to chemo-, radio- and immunotherapies as well, especially during treatment. This makes them a high value target in metastatic TNBC (mTNBC). Importantly, evidence points that cancer stemness disproportionately affects AA-TNBC more than EW-TNBC women with higher rates of recurrence and mortality in AA-TNBC than EW-women. It is imperative that cancer stemness disparity should be determined in detail in order to target the TNBC more effectively in AA-TNBC patients. Tumors with high expression of BCSC stemness markers (ALDH and CD44) demonstrate the worst clinical outcomes in TNBC patients. ALDH isoenzymes are disproportionately more expressed in AA-TNBC than EW- TNBC. Our target, the mRNA helicase, the eukaryotic initiation factor 4A1 (eIF4A1) is expressed by both BCSCs and non-BCSCs, making it an ideal target to eliminate both compartments simultaneously to prevent plastic interconversion between them. We previously demonstrated that eIF4A1 can orchestrate cancer stemness and chemoresistance in vitro. In this study, we propose that the helicase activity of eIF4A1 disproportionately regulates cancer stemness and chemoresistance in AA-TNBC than EW-TNBC patients. In aim1, we will determine a cancer disparity role for eIF4A1 in the regulation of pluripotency/cancer stemness and chemoresistance in vitro. In aim2, we will target the helicase activity of eIF4A1 pharmacologically to antagonize primary and metastatic tumor burden using patient-derived xenograft (PDX) TNBC models of AA, EW, and Hispanic women. This will facilitate obtaining preliminary data for a future R01 grant addressing the role of eIf4A1 in cancer disparity in detail.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
