Researchers have found that a now-discontinued drug used to treat the symptoms of Parkinson’s disease may be effective at treating metastatic breast cancer and the brain metastases that can often result. The repurposed drug has the potential to be a novel therapeutic in the fight against cancer.
Breast cancer is one of the major causes of brain metastases and the most common cause of cancer-related death in women globally. Breast cancer brain metastases can be difficult to treat because the body’s protective blood-brain barrier (BBB) is often impermeable to drugs that will kill the cancer cells.
In a new study, researchers at Northwestern Medicine in the US went searching for a drug that could cross the BBB and was effective at killing cancer cells and appear to have struck gold.
“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,” said Jawad Fares, lead author of the study. “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.”
The researchers screened more than 320 FDA-approved central nervous system small-molecule inhibitor drugs known to cross the BBB. Among the drugs tested, metixene – a drug used to treat the symptoms of Parkinson’s disease but now discontinued – was identified as a top candidate for killing cancer cells in various subtypes of metastatic breast cancer and brain metastases.
Administering metixene to mice not only decreased the size of breast cancer tumors but also increased the lifespan of mice with multi-organ site metastases, solitary and multiple brain metastases.
The researchers observed that metixene induced incomplete autophagy – where cellular ‘rubbish’ accumulates and is not recycled and reused – in the cancer cells by activating the NDRG1 protein, leading to cell death or apoptosis. Knocking out the NDRG1 gene using CRISPR-Cas9 gene editing led to autophagy completion and reversal of the metixene apoptotic effect.
“The study highlights the potential clinical significance of metixene as a promising therapeutic agent for the treatment of metastatic cancer and brain metastases,” Fares said. “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 clinical trials.”
The study was published in The Journal of Clinical Investigation.
Source: Northwestern Medicine
