# FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $41,668

## Abstract

Abstract
The training goal of this diversity supplement grant is for Daisy Medina to gain valuable skills in translational
research methods and further her career development in such a way that will allow her to become a successful
independent researcher. The research goal of this diversity supplement award will be to investigate the role of
FOXM1-associated signaling in supporting rescue DNA repair pathways (e.g. alt-NHEJ) and consequently breast
cancer growth, progression and drug resistance through the use of FOXM1 inhibitor that we have developed.
A significant proportion of ER+ BCs, which account for ~70% of all BCs, initially respond to antiestrogens or
aromatase inhibitors, but become therapy resistant and progress to incurable metastases. Furthermore, TNBC
accounts for 10-20% of BC cases, commonly occur in younger women, have higher propensity to relapse and
contribute to disproportionate number of deaths in BC. FOXM1 is a proto-oncogene that is highly expressed in
ER+ and TNBCs and promotes tumor growth, progression as well as therapy resistance. As part of the parent
grant, we propose that FOXM1 may promote ER+ and TNBC growth and therapy resistance by supporting
alternative (backup) DNA repair pathways; and a novel FOXM1 inhibitor (Imipramine Blue; IB) that we recently
developed, will block FOXM1’s DNA repair ability and sensitize breast cancer cells to standard of care therapies.
To achieve these goals, the trainee will focus her efforts on the following aims as part of the contributions to this
supplement.
Aim 1. To characterize the IB-target protein interactions and determine the mechanism(s) by which IB
regulates its target genes in TNBC and ER+BC. In this aim, we will establish whether IB treatment depletes
FOXM1 by directly binding to the protein or whether it acts downstream and disrupts positive feedback activation
of FOXM1 using biophysical, structure-based and molecular biology approaches. Mechanistic studies will also
determine whether IB has FOXM1-independent effects.
Aim 2. To elucidate the mechanism(s) by which IB inhibits TNBC and ER+BCs growth/metastasis and
sensitizes chemotherapy and anti-endocrine therapy response. In this aim, we will test the hypothesis that
IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting
alternative/backup DNA repair pathways that these cancers employ to survive and progress. To accomplish
these goals, we will use target gene overexpression, knockdown cell models, biochemical, immunofluorescence,
radiolabeled ligand binding, confocal microscopy and DNA repair assays.
Aim 3. To test the hypothesis that IB is a safe and viable therapeutic for treating TNBC and ER+BC. In this
aim, we will rigorously test the therapeutic potential of IB in blocking the growth and progression of TNBC and
ER+BC; by which improving the efficacy of chemotherapy using patient derived xenografts (PDX) in humanized
mice and by using human breast cancer explant (PDEx) studies.
Succe...

## Key facts

- **NIH application ID:** 10533572
- **Project number:** 3R01CA239227-03S1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Manjeet Kumar Rao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,668
- **Award type:** 3
- **Project period:** 2019-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533572

## Citation

> US National Institutes of Health, RePORTER application 10533572, FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers (3R01CA239227-03S1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10533572. Licensed CC0.

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