by McMaster University

Credit: CC0 Public Domain

In a study published 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 Center for Discovery in Cancer Research, says brain metastases are becoming increasingly prevalent and are extremely fatal, with 90% 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 endeavor, 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.

This large-scale study has been driven largely by staff, students, and trainees at both the Boris Family Medicinal Chemistry Laboratory and the Singh Lab.

One such trainee is Agata Kieliszek, a postdoctoral fellow in the Singh Lab and the lead author on the new paper. Kieliszek says she is moved by the fact that this study may eventually lead to an all-new standard of care.

"Brain metastases are the most common brain tumors in adults, and the standard of care is largely palliative," she explains. "With this work, we've uncovered a target for slowing brain metastasis outgrowth, which, with further research, could offer an alternative treatment option for patients who are otherwise limited to palliation."

Beyond the paradigm-changing potential of their findings, the researchers are also optimistic about the broader implications of this study.

"The compounds that we're looking at prevent spread to the brain, but the principles of metastasis are potentially similar across other organs," Magolan says. "I am hopeful that this program might open a gateway to anti-metastasis therapies that can prevent other types of cancer spread."

The research team intends to spin-out a new start-up company that will focus on translating this research into a first-in-class precision medicine against brain metastasis.

More information: De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases, Cell Reports Medicine (2024). DOI: 10.1016/j.xcrm.2024.101755. www.cell.com/cell-reports-medi … 2666-3791(24)00485-3

Journal information: Cell Reports Medicine 

Provided by McMaster University