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

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2022 · $408,726

## Abstract

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.

## Key facts

- **NIH application ID:** 10366263
- **Project number:** 1R01CA258682-01A1
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Dayanidhi Raman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $408,726
- **Award type:** 1
- **Project period:** 2022-08-09 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366263

## Citation

> US National Institutes of Health, RePORTER application 10366263, Targeting eIF4A1 in drug-resistant breast cancer stem-like cells (1R01CA258682-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366263. Licensed CC0.

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