Researchers Jakob Magolan (left) and Sheila Singh (right) have identified a new therapeutic approach to preventing metastatic brain cancer.
Photo Credit: Faculty of Health Sciences / McMaster University
Scientific Frontline: Extended "At a Glance" Summary: Selective IMPDH2 Inhibition in Metastatic Brain Cancer
The Core Concept: Researchers have developed novel, preventive therapeutics designed to intercept and destroy metastasizing cancer cells before they can form secondary tumors in the brain. This approach targets specific enzymatic mechanisms to block the neurological spread of primary lung, breast, skin, and other cancers.
Key Distinction/Mechanism: Previous oncological treatments targeted the general inosine monophosphate dehydrogenase (IMPDH) enzyme, which caused severe side effects by inhibiting healthy cellular function. This new approach selectively inhibits the IMPDH2 isoform; because IMPDH2 is vital for cancer cells initiating brain metastases but remains scarce in healthy tissue, the new compounds eliminate rogue cells without widespread toxicity.
Major Frameworks/Components:
- Isoform-Selective Inhibition: Targeting only the IMPDH2 enzyme variant to achieve a high degree of safety and selectivity over traditional pan-IMPDH inhibitors.
- Metastatic Interception: Shifting the treatment paradigm for metastatic brain cancer from palliative care to a preventive model that stops migrating cancer cells in transit.
- Pharmacokinetic Optimization: Designing and synthesizing compounds capable of maintaining effective half-lives, penetrating the blood-brain barrier, and functioning synergistically with existing oncological therapies.
Branch of Science: Oncology, Biochemistry, Medicinal Chemistry, and Pharmacology.
Future Application: The collaborative medicinal chemistry team is currently refining hundreds of synthesized drug candidates, aiming to advance the most optimized molecules into human clinical trials to protect high-risk cancer patients from brain metastases.
Why It Matters: Metastatic brain cancer is the most prevalent brain tumor in adults, presenting a grim prognosis with a 90 percent mortality rate within one year of diagnosis. By neutralizing metastasizing cells early, this highly targeted therapy has the potential to transform a fatal complication into a fully preventable condition.
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 (PNAS), 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 tumors 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 tumor in adults and comes with an extremely grim outlook, with 90 percent of patients passing away within just one year of diagnosis.
The current treatment paradigm is largely palliative, she adds, which is why her group is focusing instead on developing preventive 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 tumor, 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.
Singh’s group is targeting IMPDH2—one of two forms of the enzyme that is vital to the cells that start brain metastases. Unlike its other form, IMPDH2 is not abundant in healthy tissue, indicating that drugs that selectively target IMPDH2 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 is 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.”
Funding: 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.
Published in journal: Proceedings of the National Academy of Sciences
Authors: Agata M. Kieliszek, Erika Apel, Suky Zheng, Mathew Piotrowski, Danny Chui, Sébastien Alazet, Saeideh Shamsi, Daniel Mobilio, Jarrod W. Johnson, Laura Escudero, Kurt Vandevoorde, Lin Mei, Mariana Acevedo, Juliette Sabbatani, Oliver A. Kent, Fatemeh Dordahan, Arun Yadav, Bruce MacKay, Kevin Leguay, Kathleen J. Berger, Petar Miletic, Kui Zhai, Patrick Ang, Ariana Huebner, Shawn C. Chafe, Claudio Sturino, Janek Szychowski, Chitra Venugopal, Joseph Mancini, Amie L. Phinney, Jakob Magolan, and Sheila K. Singh
Source/Credit: McMaster University | Blake Dillon
Edited by: Scientific Frontline
Reference Number: ongy061926_01
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