Virtually all high-grade, aggressive gliomas in adults accumulate massive amounts of a metabolite called guanidinoacetate (GAA) that overstimulates nearby neurons and promotes tumor growth, according to new research from scientists at\u00a0Children\u2019s Medical Center Research Institute at UT Southwestern (CRI) published in\u00a0Cell.<\/p>\n
![\"Scientists](\"https:\/\/www.newsbeep.com\/nz\/wp-content\/uploads\/2026\/09\/ImageForNews_847162_17897471804344132.png\" "\\"Scientists")
\nFrom left, Samuel McBrayer, Assistant Professor in Children\u2019s Medical Center Research Institute at UT Southwestern and of Pediatrics \u2013 along with McBrayer Lab researchers Shuangcheng Alivia Wu, Ph.D., Yi Xiao, Ph.D., and Charles K. Edgar, Ph.D. \u2013 examine a histological slide. Image Credit: Children\u2019s Medical Center Research Institute at UT Southwestern<\/p>\n
Researchers discovered the 100-fold accumulation of GAA happens when tumors hyperactivate the enzyme that creates GAA. With cancer cells oversaturated, the GAMT enzyme can\u2019t convert the extra GAA into creatine. Excess GAA is released into the tumor microenvironment and stimulates neurons that promote tumor growth.<\/p>\n
GAA accumulation in these tumors mimics a known inborn error of metabolism called GAMT deficiency which \u2013 just like high-grade gliomas \u2013 results in seizures and neurological symptoms.<\/p>\n
\u201cOur work addresses a long-standing question in cancer neuroscience. We knew there is increased activity of neurons in brain tumors, but we had an incomplete understanding of how brain tumors cause that increase in activity,\u201d said study leader\u00a0Samuel McBrayer, Ph.D., Assistant Professor in CRI and of\u00a0Pediatrics.<\/p>\n
Following this discovery, researchers will test whether a clinically approved dietary therapy for GAMT deficiency could block GAA accumulation in patients with high-grade glioma.<\/p>\n
\u201cWe are going to take these laboratory findings and immediately see how to benefit patients,\u201d said Kalil G. Abdullah, M.D., study first author, System Director for Central Nervous System<\/a> Cancer at Northwell Health and former UT Southwestern faculty member.\u00a0<\/p>\n Our trial will modify the diets of patients before they undergo surgery for a glioma, and we will know very quickly how the diet changes the tumor itself by analyzing brain tumor tissue from their surgery.\u201d<\/p>\n Kalil G. Abdullah, M.D., Study First Author and System Director for Central Nervous System Cancer, Northwell Health<\/p>\n If the dietary modification successfully reduces GAA levels in tumors, Dr. McBrayer said, subsequent studies could test whether dietary change improves therapy responsiveness and survival in patients.<\/p>\n Scientists discovered that when GAA seeps out of cancer cells, it binds to and activates receptors on neurons near the tumor. In response, neurons are stimulated, causing them to release chemical and electrical signals that drive glioma cell proliferation.<\/p>\n In the study, researchers used multiple experiments to show GAA promotes the growth of brain tumors by activating adjacent neurons. When scientists blocked the enzyme making GAA in glioma cells, GAA levels fell, neuronal activity dropped, and tumor growth slowed. If neurons adjacent to brain tumors were activated by other means, neurons promoted tumor growth even in the absence of GAA. Also, when cancer cells were grown in the absence of adjacent neurons, depleting GAA did not slow the proliferation of cancer cells.<\/p>\n \u201cA major benefit of doing research as part of the\u00a0CRI Genetic and Metabolic Disease Program\u00a0is that we are able to leverage insights from well-characterized inborn errors of metabolism to understand how metabolism goes awry in brain tumors,\u201d Dr. McBrayer said. \u201cBy comparing these diseases, we are better able to pinpoint the causes and consequences of metabolic changes in glioma, ultimately informing new ways to treat these cancers.\u201d<\/p>\n Dr. McBrayer is an Investigator in the Peter O\u2019Donnell Jr. Brain Institute and a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center at\u00a0UT Southwestern. He is also a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar. He was honored with a Distinguished Scientist Award in 2021 from the\u00a0Sontag Foundation for his work on brain tumors.<\/p>\n Additional first authors include Charles K. Edgar, Ph.D., Perot Family Scholars Medical Scientist Training Program graduate student at UT Southwestern, Shuangcheng Alivia Wu, Ph.D., CRI postdoctoral fellow, and Yi Xiao, Ph.D., National Institutes of Health Pathway to Independence fellow and CRI postdoctoral fellow, all McBrayer Lab researchers; and Kenji Miki, M.D., postdoctoral fellow at Northwell Health.<\/p>\n Other study contributors include Ralph J. DeBerardinis, M.D., Ph.D., Professor and Director of the\u00a0Eugene McDermott Center for Human Growth and Development, CRI, Pediatrics, co-Leader of the Cellular Networks in Cancer Research Program in the Simmons Comprehensive Cancer Center, and Director of the\u00a0CRI Metabolomics Shared Facility; Kimberly M. Huber, Ph.D., Professor of\u00a0Neuroscience; Jay R. Gibson, Ph.D., Professor of Neuroscience; Tara Barron, Ph.D., Assistant Professor of\u00a0Pathology; Benjamin Levi, M.D., Professor of\u00a0The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, CRI,\u00a0Plastic Surgery, and\u00a0Surgery; Thomas P. Mathews, Ph.D., Associate Professor in CRI and Pediatrics, and Assistant Director of the CRI Metabolomics Shared Facility; Feng Cai, Ph.D., Assistant Professor in CRI and Pediatrics; Lin Xu, Ph.D., Assistant Professor of\u00a0Health Data Science and Biostatistics\u00a0in the\u00a0Peter O\u2019Donnell Jr. School of Public Health\u00a0and of Pediatrics; Bradley C. Lega, M.D., Professor of\u00a0Neurological Surgery,\u00a0Neurology, and\u00a0Psychiatry<\/a>; Shang Ma, Ph.D., Assistant Professor in CRI, the McDermott Center, and Pediatrics; Denise Ramirez, Ph.D., Associate Professor of Neurology; Prithvi Raj, Ph.D., Associate Professor of\u00a0Immunology; Kimmo Hatanpaa, M.D., Ph.D., Professor of Pathology; and Toral Patel, M.D., Associate Professor of Neurological Surgery, Neurology, and\u00a0Radiation Oncology.<\/p>\n This research was funded by the National Institutes of Health, Oligo Nation, Sarkes and Mary Tarzian Charitable Foundation Inc., CPRIT, The Sontag Foundation, Jonesville Foundation, The Nick Gonzales Foundation for Brain Tumor Research, a Human Frontier Science Program fellowship, a Burroughs Wellcome Fund Career Award for Medical Scientists, a Lubin Family Foundation Scholar Award, and the Spanish Ministerio de Ciencia, Innovaci\u00f3n y Universidades, and Junta de Andaluc\u00eda, Consejer\u00eda de Salud.<\/p>\n Dr. McBrayer has a financial interest in Gliomet.<\/p>\n Source:<\/p>\n