MCW Cancer Center’s Balaraman Kalyanaraman, PhD, Professor of Biophysics, and an international team of scientists recently wrote a in Cancer Communications to highlight the potential benefits of the MCW-created drug, mitochondria-targeted atovaquone (Mito-ATO). Their research, the first of its kind, reveals how Mito-ATO plays a crucial role in improving cancer treatment by altering and reprogramming immune cells, ultimately making immunotherapy more potent against tumors.
“Atovaquone (ATO) is an FDA-approved drug used to prevent malaria, and was recently repurposed in cancer research to treat glioblastoma. It targets tumor mitochondria but is effective at slightly higher concentrations. Our MCW team modified the structure of ATO so the new compound, Mito-ATO, is nearly 100-times more potent in inhibiting mitochondrial respiration and proliferation of tumor cells,” explained Dr. Kalyanaraman. “The new drug has shown promise in lung cancer and breast cancer models, and is likely to work against other tumors as well.”
“Mito-ATO enhances the activity of immune cells that fight tumors while suppressing the activity of immune cells that support tumor growth, making it a potentially powerful tool in cancer treatment. Since it is more potent against human cancer cell lines than atovoquone, we believe Mito-ATO can have great clinical potential,” he added.
This work builds on an existing led by MCW’s Gang Cheng, PhD, Assistant Professor of Biophysics. The findings, which were published in Scientific Reports in 2020, showed Mito-ATO is capable of stopping certain immune cells that support tumors (myeloid-derived suppressor cells), and activating other immune cells that fight against tumors (cytotoxic antitumor T cells). To better understand Mito-ATO’s influence on immune cells, the research team used a technology called single-cell RNA sequencing to evaluate lung tumors in mice. They discovered that Mito-ATO:
- Changes the activity of genes related to energy production (OXPHOS) in immune cells;
- Increases energy production in anti-tumor immune cells, while decreasing energy production in pro-tumor immune cells; and
- Influences metabolic pathways related to energy production and cell death.
“Mito-ATO is proven to be effective for inhibiting tumor metastasis in mice xenografts and is ready to be evaluated in our clinics, primarily in combination with radiation therapy or immunotherapy because of its ability to inhibit tumor hypoxia (increased oxygen levels in tumors due to inhibition of mitochondrial respiration),” said Dr. Kalyanaraman. “We welcome collaborations with MCW researchers, and are happy to supply this innovative drug to those working in cancer biology, immuno-oncology, and related areas of research.”
Dr. Kalyanaraman thanks Ming You, MD, PhD, Center for Cancer Prevention, Houston Methodist Research Institute of Texas, and Micael Hardy, PhD, Aix-Marseille Université of France, for their contributions to this important work.