# Mitochondrial metabolism as a target of breast cancer therapy

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2021 · —

## Abstract

Significance – Breast cancer (BC) is one of the most common causes of cancer deaths for women with
increasing incidence among women Veterans in the VA Health Care System. Patient survival has improved
dramatically for primary BC but metastatic BC, for which targeted agents are usually not available, is common
in African-American Veterans and is largely incurable. Most BC treatments target proliferating tumor cells that
rely on glycolysis to fuel their metabolic needs. However, metastatic BC may exhibit a cancer stem cell phenotype
with considerable dormancy and acquired drug resistance. These BC, including triple negative BC (TNBC), are
often dependent on mitochondrial respiration (oxidative phosphorylation; oxphos) to generate energy and
promote survival. Since there are no targeted therapies for TNBC and since most mitochondrial-targeting drugs
exhibit substantial toxicity, there is a need to find new and safer therapeutic agents. Using a direct drug discovery
approach and computer-assisted drug design (CADD), we identified novel small molecules that interfere with
protein:DNA binding and transcriptional activity. While normal epithelial cells were relatively resistant, a lead
compound (CADD522) inhibited BC cell proliferation and tumorsphere formation, delayed tumor growth and
metastasis in vivo, and inhibited mitochondrial adenosine triphosphate (ATP) synthase and respiration (oxygen
consumption) while increasing the levels of reactive oxygen species (ROS).
Premise – Understanding the molecular mechanisms of targeting mitochondrial ATP synthase to elevate ROS
in cancer cells will likely result in novel therapeutics against metastatic BC. Patients with drug-resistant, dormant
or metastatic disease could benefit from a therapeutic approach that targets mitochondrial oxphos by
inhibiting ATP synthase. Therefore, we propose the hypothesis that targeting mitochondrial metabolism with
a novel ATP synthase inhibitor will inhibit BC tumor progression and metastasis by lowering ATP levels, reducing
cellular respiration, and increasing ROS damage for therapeutic benefit.
Specific Aims – Specific Aim 1: Define the mechanistic basis for CADD522-mediated ATP synthase inhibition in
restraining BC tumor cell proliferation. Mitochondrial oxygen consumption rate (OCR), global gene expression
profiles and direct targeting of ATP synthase will be defined. Specific Aim 2: Determine the mechanisms through
which CADD522-mediated OCR inhibition increases reactive oxygen species (ROS) to reduce glucose utilization.
Redox balance, pyruvate dehydrogenase (PDH) activity, and TCA cycle flux will be measured. Specific Aim 3:
Define the translational potential of mitochondrial targeting with CADD522 to promote ROS damage and inhibit
BC growth and metastasis. In vitro toxicological assays and in vivo tumor models will assess translational
potential after oral administration of a novel therapeutic agent.
Overall Impact – Elucidating how reprogrammed cancer cell metabolism p...

## Key facts

- **NIH application ID:** 10174751
- **Project number:** 5I01BX004904-02
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** ANTONINO PASSANITI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174751

## Citation

> US National Institutes of Health, RePORTER application 10174751, Mitochondrial metabolism as a target of breast cancer therapy (5I01BX004904-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10174751. Licensed CC0.

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