Researchers uncover possible new treatment to target a devastating childhood brain cancer

Professor Peter Lewis
Photo Credit: Courtesy of University of Wisconsin–Madison

Using fruit flies, University of Wisconsin–Madison researchers have developed a new model for investigating the genetic drivers of a rare but aggressive brain tumor in children. The work has already identified potential treatment targets for the deadly cancer that has previously had few therapeutic options.

“Right now, these tumors are incurable, and the standard of care hasn’t changed for 30 years,” says Peter Lewis, a professor in the Department of Biomolecular Chemistry.

The cancer is called pediatric diffuse midline glioma. As its name suggests, the malignancy arises along the midline of the brain or spinal cord and infiltrates surrounding tissue in a way that makes it impossible to remove with surgery. Instead, typical treatment revolves around radiation therapy, and that extends a patient’s life by just months or at most a few years.

Professor Peter Lewis: “What we found might extend well beyond these very rare childhood tumors into more common ones.”

The limited treatment options have driven researchers to more closely examine the genetic mutations that cause the cancer to develop in the first place, with an eye on finding ways to disrupt that process. 

In the case of diffuse midline glioma, previous research identified mutations in certain DNA-packaging proteins as a likely culprit.

“The mutation in these proteins really derails their gene control systems,” says Lewis. In particular, they disrupt a system that’s so evolutionarily ancient that it operates almost identically in species as distinct as humans and fruit flies.

Professor Melissa Harrison
Photo Credit: Courtesy of University of Wisconsin–Madison

Professor Melissa Harrison, whose lab uses fruit flies to study all sorts of cell development processes, saw an opportunity to study how these mutated proteins — called oncoproteins — actually cause the gene control system to go haywire.

“We thought, wouldn’t it be cool if we could model these oncoproteins in fruit flies?” says Harrison. “We all have a common ancestor, and this basic gene repression machinery is identical or similar enough between humans and fruit flies that we can actually put the oncoproteins that are driving these tumors in humans into fruit flies and see what they do.”

Professor Melissa Harrison: “I think it’s a strength of UW–Madison that leadership is so supportive of collaborations.”

So, with support from the UW Carbone Cancer Center and National Cancer Institute, Lewis’s and Harrison’s labs got to work.

Using tools that allowed them to turn on specific proteins in particular tissues, the researchers expressed the oncoproteins in fruit flies’ eyes and wings, which caused developmental defects. They then screened hundreds of other genes to see which ones made the defects worse or better.

“We discovered dozens of these interacting pathways that either worsened or eased the damage that was caused by these oncoproteins,” says Harrison. “These included, notably, some that would help restore the overall development of the wing or eye.”

Those genes responsible for restoring normal development are strong candidates for future treatment targets in cancer patients, according to Harrison and Lewis — and not just for the pediatric gliomas.

“This same gene control system is implicated as a driver of many human tumors, including diffuse large B-cell lymphoma, different types of prostate cancers, and other gliomas,” says Lewis. “So, what we found might extend well beyond these very rare childhood tumors into more common ones.”

Much work remains before researchers can identify potential therapeutics, but the new findings, recently published in the journal Genetics, provide a useful roadmap to follow. It’s a result that Lewis and Harrison both feel was made possible by the unusually collaborative research environment at UW–Madison.

“I think it’s a strength of UW–Madison that leadership is so supportive of collaborations and recognizes their strength,” says Harrison. “For me, having Peter here as a collaborator is a huge benefit of being at this university.”

Lewis adds: “While we can’t change the funding rates from the federal government, what we can do is find joy in the science and collaborators who are similarly intellectually invested in the questions we’re asking.”

Funding: National Institutes of Health (F30CA260987; (R01CA266861; P01CA196539; P41GM132087; P400D018537), and the University of Wisconsin Comprehensive Cancer Center Support Grant.

Published in journal: Genetics

Title: Novel modifiers of oncoprotein-mediated Polycomb inhibition in Drosophila melanogaste

Authors: Samuel D Krabbenhoft, Tyler E Masuda, Yadwinder Kaur, Truman J Do, Siddhant U Jain, Peter W Lewis, and Melissa M Harrison

Source/Credit: University of Wisconsin–Madison | Will Cushman

Reference Number: bmed101525_01

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