Northwestern Medicine investigators have identified a novel therapeutic agent that is effective in treating metastatic breast cancer and brain metastases with minimal side effects, according to a recent study published in the Journal of Clinical Investigation.
The study, led by Maciej Lesniak, MD, chair and the Michael J. Marchese Professor of Neurosurgery, found that metixene, a central nervous system small-molecule inhibitor drug, induced cancer cell death in mouse models of different metastatic breast cancer subtypes and extended survival in mice with brain metastases.
“The significance of this project lies in its potential to address a pressing clinical challenge: the treatment of brain metastases, particularly in the context of breast cancer. It offers hope for improving the quality of life and survival outcomes for a substantial number of patients affected by brain metastases, a common and serious complication of cancer. The identification of a novel therapeutic agent, metixene, and its mechanistic insights add a promising dimension to the field of cancer research and treatment,” said Jawad Fares, MD, MSc, a neurosurgery resident at Northwestern Medicine and a postdoctoral fellow in the Lesniak laboratory who was lead author of the study.
Breast cancer is one of the major causes of brain metastases and is also the most common cause of cancer-related death in women worldwide, according to the World Health Organization. A lack of clinical trials and new therapeutic options has also slowed progress in treating patients with breast cancer brain metastases.
In the current study, the investigators screened more than 320 FDA-approved drugs known to cross the blood-brain barrier, which prevents foreign substances, including most drugs, from entering the brain. Among the drugs tested, metixene — an antiparkinsonian drug — was identified as a top candidate for killing cancer cells in various subtypes of metastatic breast cancer and brain metastases.
In a series of in vivo experiments, metixene not only decreased the size of breast tumors in mice, but also increased the lifespan of mice with multi-organ site metastases, intracranial solitary metastasis, and multiple brain metastases.
Subsequent functional analysis further showed that metixene induced “incomplete autophagy” — when waste accumulates inside a cell and fails to be recycled and reused — in cancer cells by activating the NDRG1 protein, which caused the cancer cells to trigger their own death.
Using CRISPR-Cas9 gene editing to knockout NDRG1 in breast cancer cell lines also led to autophagy completion and the reversal of metixene-induced apoptosis, or programmed cell death, in the cancer cells, according to the authors.
“The study highlights the potential clinical significance of metixene as a promising therapeutic agent for the treatment of metastatic cancer and brain metastases. The drug was noted for having minimal reported side effects in humans, which makes it a strong candidate for consideration in clinical translation, i.e., further investigation and potential use in human clinical trials,” Fares said.
Co-authors include Crismita Dmello, PhD, research assistant professor of Neurological Surgery, Peng Zhang, PhD, assistant professor of Neurological Surgery, Atique Ahmed, PhD, the Allen Buckner Kanavel Professor of Neurosurgery, Jason Miska, PhD, assistant professor of Neurological Surgery,
Irina Balyasnikova, PhD, professor of Neurological Surgery, C. David James, PhD, Professor Emeritus of Neurological Surgery, Adam Sonabend, MD, associate professor of Neurological Surgery, and Amy Heimberger, MD, PhD, the Jean Malnati Miller Professor of Brain Tumor Research.
Lesniak, Dmello, Zhang, Ahmed, Miska, Balyasnikova, James, Sonabend and Heimberger are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was supported by National Institutes of Health grants P50CA221747, R35CA197725, R01NS87990 and R01NS093903.
