A research team based at McMaster University has identified a more precise and effective way to prevent cancer from spreading to the brain, building on a promising new therapeutic strategy first reported by the same group last year.
In a new study published today in the Proceedings of the National Academy of Sciences, researchers have detailed the development of novel drug candidates that target a key enzyme implicated in the spread of lung, breast, skin, and other cancers to the brain.
The new drug candidates are designed to intercept rogue cancer cells before they depart other primary tumours and ultimately travel toward the brain.
Sheila Singh, a professor in McMaster’s Department of Surgery and principal investigator on the new study, says that this type of cancer — called metastatic brain cancer — is the most common type of brain tumour in adults and comes with an extremely grim outlook, with 90 per cent of patients passing away within one year of diagnosis.
The current treatment paradigm is largely palliative, she adds, which is why her group is focusing instead on developing preventative interventions.
“By identifying patients who are at high risk of developing this type of brain cancer and trying to intercept the metastasizing cells before they can even form a brain tumour, we can transform this fatal disease into one that is entirely preventable,” says Singh, whose work is based out of McMaster’s Centre for Discovery in Cancer Research and supported by NexusHealth.
The new therapeutics, which are being developed by McMaster spin-out company Block Biosciences, target an enzyme called IMPDH2, which plays a critical role in the development of brain metastases.
IMPDH has long been explored as a druggable target in cancer research, and some drug candidates have even advanced as far as human trials; however, drugs that block IMPDH have historically caused significant side effects because they also inhibit healthy cells.
But Singh’s group is targeting IMPDH2 — one of two forms of the enzyme that is vital to the cells that start brain metastases. But, unlike its other form, IMPDH2 is not abundant in healthy tissue, indicating that drugs that target IMPDH2 selectively will eliminate rogue cancer cells without causing major side effects.
“Taking a highly selective approach to eliminating these cancer-initiating cells allows us to strike the right balance between effectiveness and safety,” says Agata Kieliszek, a postdoctoral fellow at McMaster and head of biology and operations at Block Biosciences.
Drug development is now underway, jointly led by medicinal chemists at McMaster and Block. The collaborative research team has already designed and synthesized several hundred IMPDH2-targeting drug candidates and are selecting the best of these compounds to advance further down clinical development pathways.
Jakob Magolan, a professor of biochemistry and biomedical sciences at McMaster and head of chemistry at Block, is optimistic about the prospects of translating these findings into actual medicine in the future.
“Our top drug candidates now have most of the properties needed for real clinical potential,” he says. “These include staying in the body long enough to be effective, crossing the blood-brain barrier, and synergizing with existing cancer medicine for added potency. These are exciting results, but some further refinement is still needed before we can advance one of these molecules into human trials.”
This research has been supported by funding from adMare BioInnovations, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Boris Family, and McMaster University.