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MCW researchers publish collaborative study on potential intervention for lung cancer brain metastasis

Brain metastasis remains one of the leading causes of lung cancer mortality, yet the current therapies available are primarily palliative and have significant risks and toxicity. A collaborative research team from MCW, the University of Michigan, and Aix-Marseille University has a potential new intervention for lung cancer brain metastasis that has little toxicity in a mouse model.

The team published its findings in the May 17 issue of Nature Communications. As part of the study, the team modified an existing lung cancer drug – lonidamine (LND) – to mitochondria-targeted mito-lonidamine (Mito-LND), a tumor-selective inhibitor that is 100 times more potent than LND and is shown to have little toxicity. Mito-LND mitigates lung cancer and associated brain metastasis in mice by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, and inducing autophagic cell death in lung cancer cells. Collectively, these findings show that mitochondrial targeting of Mito-LND is a promising therapeutic approach for patients with either primary or metastatic lung cancer.

As a result of this work, a new collaboration is being established with a group at University of Pennsylvania to investigate the efficacy of Mito-LND in prostate cancer mouse models. MCW researchers involved in the study include Gang Cheng, PhD, research scientist II in biophysics; Qi Zhang, PhD, and Jing Pan, PhD, both assistant professors in pharmacology and toxicology; Yongik Lee, a PhD Student in pharmacology and toxicology (currently manager of Drug Discovery Science and Management at Astellas Pharma); Monika Zielonka, research technologist III in biophysics; Charles R. Myers, PhD, professor of pharmacology and toxicology; Jacek Zielonka, PhD, assistant professor of biophysics; Balaraman Kalyanaraman, PhD, the Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research, professor and chair of biophysics, and associate director of the Center for Disease Prevention Research; and Ming You, MD, PhD, Associate Provost for Cancer Research, Joseph F. Heil Jr. Professor of Oncogenesis, professor of pharmacology and toxicology, and director of the Center for Disease Prevention Research. Most of these individuals are members of the newly formed Center for Disease Prevention.

Research. Laura Kresty, PhD, associate professor at University of Michigan, and her team investigated how Mito-LND induces autophagy to promote lung cancer cell death and inhibit lung cancer progression and metastases. International collaborators include Olivier Ouari, PhD, assistant professor at Aix-Marseille University, and Micael Hardy, PhD, assistant professor at Aix-Marseille University and visiting faculty in biophysics