Researchers at McMaster University have identified a new therapeutic approach to preventing cancer from spreading to the brain.
In a new study, published recently in the journal Cell Reports Medicine, researchers Sheila Singh and Jakob Magolan discovered a critical vulnerability in metastatic brain cancer, which they say can be exploited with new drugs to prevent spread.
Singh, a professor in McMaster’s Department of Surgery and director of the Centre for Discovery in Cancer Research, says brain metastases are becoming increasingly prevalent and are extremely fatal, with 90 per cent of patients dying within one year of diagnosis. She notes that lung cancer, breast cancer, and melanoma most often result in brain metastases.
“We’re getting much better at curing these primary cancers, but even when we do, a tiny percentage of cancer cells can escape and circulate to other parts of the body, including the brain,” she explains. “When this happens, it’s often an end-stage cancer — treatment-resistant and highly evasive.”
Magolan, a professor of medicinal chemistry in McMaster’s Department of Biochemistry and Biomedical Sciences, suggests thinking of an organ as an island in an ocean, and cancer as a city developing atop it. Some cities, he says, may develop marinas full of ships to explore and settle on other islands — these ships are the rare cancer cells that can metastasize to other organs.
“We have figured out how to sink these ships while they’re in transit — and likely before they even set sail,” he says.
The interdisciplinary research team is targeting an enzyme called IMPDH, which is essential to the cancer cells that can initiate brain metastases. By designing drugs that inhibit this enzyme, they anticipate that they can stop brain metastasis from occurring.
To date, the researchers have synthesized and evaluated more than 500 candidate molecules — a huge endeavour, especially for academic laboratories.
“Typically, a discovery program in a big pharmaceutical company will make about 1,000 molecules before selecting one to advance to the final stages of pre-clinical efficacy and safety studies,” explains Magolan, who is part of the executive committee at McMaster’s Global Nexus. “We’re more than halfway through such an industrial-sized program now, with promising compounds in hand, and most of the research is being done here at McMaster.”
Of the 500-plus molecules studied to date, the research team has identified dozens with potent activity against the target enzyme. Today, they are optimizing these lead molecules even further before selecting top candidates for evaluation in animal models, which will establish the foundations for eventual human clinical trials.
