Researchers have been struggling with what fuels cancer cell growth. For more than 75 years, researchers have known that cancer cells use glucose as the major fuel, but efforts to halt cancer growth by controlling glucose levels in the brain haven’t worked.
“We identified that glucose wasn’t the only fuel being burned,” said senior author Dr. Robert Bachoo, Assistant Professor of Neurology and Neurotherapeutics, and Internal Medicine, and a member of the Harold C. Simmons Cancer Center. “Acetate can be used to generate fuel and metabolites that can then be used to make other things that the cell needs to survive and multiply.”
Researchers began with specially engineered mouse models so that the tumors grown in the brain were very similar to human tumors, especially with respect to the molecular and metabolic characteristics. They then infused both 13C-acetate and 13C-glucose into the mice and were able to show that the tumors burn acetate as fuel.
“This is the first demonstration of acetate being used by the cell in this way. The striking finding was that all cancers we studied had the same ability to burn acetate,” said Dr. Elizabeth Maher, Associate Professor of Internal Medicine, and Neurology and Neurotherapeutics, and member of the Harold C. Simmons Cancer Center and the Annette G. Strauss Center for Neuro-Oncology, who holds the Theodore H. Strauss Professorship in Neuro-Oncology. “All the tumors we studied increased expression of ACSS2, the acetate metabolizing enzyme, and the gliomas appear to be dependent on acetate for growth.”
Researchers then validated their findings in two patients with glioblastomas and two patients with brain metastases (breast and lung cancer) who were undergoing surgical resection of their tumors.
“That analysis showed that the human tumors robustly burned acetate,” said Dr. Bachoo, a member of the Annette G. Strauss Center for Neuro-Oncology, who holds the Miller Family Professorship in Neuro-Oncology. “ACSS2 may thus be a therapeutic target for these very aggressive tumors that have limited therapies available.”
Combined with related research, an accompanying Preview article in the journal Cell suggested that “the insights provided by these studies position acetate metabolism as a potentially exploitable vulnerability in cancer metabolism.”
Other UT Southwestern researchers involved included co-first authors, Dr. Tomoyuki Mashimo and Dr. Kumar Pichumani, Senior Research Scientists; Dr. Bruce Mickey, Vice Chairman and Professor of Neurological Surgery, Professor of Otolaryngology – Head and Neck Surgery and Radiation Oncology, and Director of the Annette Straus Center for Neuro-Oncology who holds the William Kemp Clark Chair of Neurological Surgery; Dr. Benjamin Tu, Professor of Biochemistry and W.W. Caruth, Jr. Scholar in Biomedical Research; Dr. Ralph DeBerardinis, Associate Professor with Children’s Medical Center Research Institute at UT Southwestern, the Eugene McDermott Center for Human Growth and Development, and Pediatrics, Sowell Family Scholar in Medical Research, who holds the Joel B. Steinberg, M.D. Chair in Pediatrics; Dr. Samuel Barnett, Associate Professor of Neurological Surgery and Otolaryngology – Head and Neck Surgery, and Co-director of the Comprehensive Skull Base Surgery Program; Dr. Kimmo Hatanpaa, Associate Professor of Pathology and a member of the Simmons Cancer Center and Strauss Center for Neuro-Oncology; Dr. Zoltan Kovacs, Assistant Professor with the Advanced Imaging Research Center; Dr. Chan Foong, Faculty Associate of Pathology; Dr. Zhiguang Huang, Post Doctoral Researcher; Research Scientists Shyam Sirasanagandla, Suraj Nannepaga; Research Associate, Dr. Vamsidhara Vemireddy, former UT Southwestern researcher Dr. Dinesh Kumar Singh, and visiting scientist, Dr. Sara Piccirillo.
The work was supported by the Cancer Prevention Research Institute of Texas, National Institutes of Health, a Harold C. Simmons Cancer Center NIH support grant and philanthropic funds from the Annette G. Strauss Center for Neuro-Oncology, the Miller Family Fund in Neuro-Oncology, the Gladie Jo Salvino Fund for Glioblastoma Research at UT Southwestern Medical Center, and the Kenny Can Foundation in Dallas.
UT Southwestern’s Harold C. Simmons Cancer Center is the only National Cancer Institute-designated cancer center in North Texas and one of just 66 NCI-designated cancer centers in the nation. The Simmons Cancer Center includes 13 major cancer-care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevent cancer worldwide. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Site, and the only Cancer Center in North Texas to be so designated.
The Annette Strauss Center for Neuro-Oncology, the cornerstone of UT Southwestern Medical Center’s Neuro-Oncology Program, is comprised of multidisciplinary cancer professionals that are largely involved in innovative clinical research trials. Researchers are actively involved in projects aimed at creating new and improving existing treatments for childhood and adult brain malignancies. Its focus is to improve treatments available for patients, both inpatients and outpatients, and conduct research of tumors of the central nervous system, including benign and malignant brain and spinal-cord tumors.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering approximately 2,800, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.
Media Contact: Gregg Shields