Unexpected Findings
Diabetes was an obvious area to look for when looking for ways to suppress glucose metabolism — the same process that drives the PFA tumors.
The researchers decided to see how a commonly used diabetes drug, metformin, would affect PFA tumor cells. Not only does it have a proven track record of safety in adults and children, it’s also increasingly being used in cancer clinical trials that target tumor metabolism, Venneti explains.
“We tried it and we found that metformin suppressed the metabolism of cancer cells and killed the cells in some PFA ependymoma tumors,” he said. “And unexpectedly, we found that metformin lowers EZHIP — the protein that caused these epigenetic changes in the first place.
“And remember that mutations don’t drive these tumors, the epigenetic changes are caused by the EZHIP protein. So this opens up a really exciting opportunity to therapeutically suppress the abnormal protein that actively causes these tumors,” he adds.
Meanwhile, when metformin was given to mice carrying patient-derived tumors, it reduced tumor metabolism, shrank the tumors and led to longer survival times in a subset of metformin-sensitive tumors.
Resistance to metformin in one cell line could be overcome with panobinostat, a drug in clinical trials for other brain cancers, the researchers report.
The next step will be to translate the lab discoveries into a clinical trial, Venneti says.
“Metformin has already been shown to be safe enough to use in other clinical trials for childhood brain cancer survivors, so that gives us a big head start in moving these findings from the lab to patient trials quickly,” he noted. .
This work was funded by the Sontag Foundation, Clinical Scientist Development Award-Doris Duke Charitable Foundation, the Hyundai Hope On Wheels Foundation, National Institutes of Neurological Disorders and Stroke (R01NS110572), the UM Taubman Institute, and the National Brain Tumor Society through the Collaborative Ependymoma Research Network (CERN) Foundation Robert Connor Dawes Scientific Fellowship Prize. Additional support for collaborative labs came from numerous organizations and foundations.
Other authors include Pooja Panwalkar, Benita Tamrazi, Derek Dang, Chan Chung, Stefan Sweha, and Siva Kumar Natarajan, all of whom share first authorship. Others on the paper include Matthew Pun, Jill Bayliss, Martin P. Ogrodzinski, Drew Pratt, Brendan Mullan, Debra Hawes, Fusheng Yang, Chao Lu, Benjamin R. Sabari, Abhinav Achreja, Jin Heon, Olamide Animasahun, Marcin Cieslik, Christopher Dunham , Stephen Yip, Juliette Hukin, Joanna J. Phillips, Miriam Bornhorst, Andrea M. Griesinger, Andrew M. Donson, Nicholas K. Foreman, Hugh JL Garton, Jason Heth, Karin Muraszko, Javad Nazarian, Carl Koschmann, Li Jiang, Mariella G. Filbin, Deepak Nagrath, Marcel Kool, Andrey Korshunov, Stefan M. Pfister, Richard J. Gilbertson, C. David Allis, Arul Chinnaiyan, Sophia Y. Lun, Stefan Blüml and Alexander R. Judkins.
Cited article: Targeting Integrated Epigenetic and Metabolic Pathways in Deadly PFA Ependymomas in Children, Science Translational Medicine. DOI: 10.1126/scitranslmed.abc0497
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