# Combine mitochondrial gene therapy and synthetic lethal chemotherapy to treat triple-negative breast cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $587,453

## Abstract

SUMMARY
Triple-negative breast cancers (TNBCs) are highly aggressive and standard cytotoxic chemotherapies (e.g.
anthracycline-taxane) are the main treatment strategies in clinics. Our previous research and literature
demonstrated that poly (ADP-Ribose) polymerase inhibitors (PARPi) as single agents or in combination with
epidermal growth factor receptor inhibitor (EGFRi) induced a contextual synthetic lethality and reduced TNBC
metastsis by inhibiting the repair of DNA damage. Our clinical trial showed that veliparib (PARPi)/lapatinib
(EGFRi) achieved a 24% response rate in TNBC patients with wildtype BRCA1/2. Despite these achievements,
TNBC cells often develop drug resistance to chemotherapies, have low patient response rate, and regrow after
primary treatment. Novel strategies that can effectively treat TNBCs are urgently needed. Mitochondria are the
powerhouse of cells and play a pivotal role in regulating cell functions, rendering them a promising oncological
target. Destroying mitochondrial function, such as directly depolarizing the inner mitochondrial membrane (IMM)
potential via synthesized heterologous genes, can bypass the repair of signaling transduction pathways, trigger
a point-of-no-return cancer cell death, and subsequently prevent the development of drug resistance. We
recently developed a mitochondrial luminoptogenetics (mLumiOpto) technology by synthesizing the
heterologous light-gated channelrhodopsin in IMM and an engineered luciferase in cytoplasm, which induces
IMM depolarization through opening mitochondrial channelrhodopsin with luciferase-luciferin emitted
endogenous blue bioluminescence. Preliminary studies showed that mLumiOpto effectively depolarized
mitochondria in TNBC cell lines representing multiple subtypes, resulted in persistent DNA damage, and
significantly reduced tumor burden in three TNBC xenograft models. Applying our dual-targeted delivery vehicle,
i.e. EGFR/CD276 monoclonal antibodies tagged exosome-associated adeno-associated virus (mAb-Exo-AAV),
and cancer-specific promoter (cfos) in mLumiOpto achieved high TNBC specificity, functional expression, and
minimal undesirable systemic toxicity. The objective of this project is to harness the combination of targeted
mLumiOpto that is delivered with mAb-Exo-AAV and PARPi to eliminate TNBC cells in vivo. The hypothesis is
that the combined mLumiOpto/PARPi integrates multiple anti-cancer mechanisms, i.e., IMM depolarization, DNA
damage and inhibition of repair, and tumoral immunity. Specifically, large-scale dual-targeted mLumiOpto will be
generated and characterized; treatment dosage and strategy will be optimized; and anti-cancer efficacy will be
evaluated in TNBC primary xenograft model and distant metastatic model (Aim 1). Furthermore, the synergistic
effects of mLumiOpto/PARPi will be assessed and the underlying mechanisms will be investigated in
immunocompetent models (Aim 2). Finally, the metastasis reduction and heterogeneous TNBC treatment
efficacy wi...

## Key facts

- **NIH application ID:** 10435099
- **Project number:** 1R01CA262028-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Xiaoguang Margaret Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $587,453
- **Award type:** 1
- **Project period:** 2022-06-10 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435099

## Citation

> US National Institutes of Health, RePORTER application 10435099, Combine mitochondrial gene therapy and synthetic lethal chemotherapy to treat triple-negative breast cancer (1R01CA262028-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435099. Licensed CC0.

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