In the News
Nov. 3, 2014 — Scientists at the Children’s Medical Center Research Institute at UT Southwestern (CRI) have identified a metabolic pathway that allows cancer cells to survive periods of stress brought on by blocking the major pathway by which cells produce energy.
Most cells survive and grow by oxidizing glucose. This pathway involves first converting glucose into a smaller molecule called pyruvate, then importing the pyruvate into the mitochondria where it supplies pathways that provide energy and building blocks for growth.
CRI researchers led by Dr. Ralph DeBerardinis sought to understand whether transfer of pyruvate into the mitochondria is required for cancer cell survival and growth. They determined that although blocking pyruvate entry did, as expected, compromise the energy state of the cell, it simultaneously activated a second pathway fueled by the amino acid glutamine.
This new pathway provided enough flow of mitochondrial metabolism that cancer cells were able to survive and, to some extent, continue to grow. The glutamine-dependent pathway involved activation of an enzyme, glutamate dehydrogenase, which was normally suppressed in cells importing pyruvate into the mitochondria.
The CRI research team used models of brain and lung cancer cell growth to demonstrate that blocking either mitochondrial pyruvate import or glutamate dehydrogenase alone was fairly well tolerated. However, blocking both pathways rapidly led to cancer cell death.
Similarly, treating mice with inhibitors of both activities simultaneously — but not either one alone — significantly reduced tumor growth. Because many solid tumors, like those in the brain and lung, likely contain regions in which access to glucose or pyruvate is compromised, the new glutamine-dependent pathway may provide a survival mechanism to avoid tumor cell starvation. If so, then blocking glutamate dehydrogenase or other steps in the pathway may provide a therapeutic benefit.
July 29, 2014 — The Howard Hughes Medical Institute has awarded nearly $5 million in research fellowships to 46 predoctoral students from 24 countries, including two Ph.D. student researchers at the Children’s Medical Center Research Institute at UT Southwestern — Liem Nguyen and Xiaolei Shi.
Read the news release.
May 22, 2014 — In a breakthrough discovery at the Children’s Medical Center Research Institute at UT Southwestern (CRI), a research team led by Ralph DeBerardinis, M.D., Ph.D., has taken a significant step in cracking the code of an atypical metabolic pathway that allows certain cancerous tumors to thrive, providing a possible roadmap for defeating such cancers.
Following up on Dr. DeBerardinis’ landmark finding in 2011, this most recent discovery identifies the triggering mechanism that plays a key role in causing a series of energy-generating chemical reactions known as the Krebs cycle to run in reverse. Read the news release.
Oct. 24, 2013 — A group of researchers including Ralph DeBerardinis, M.D., Ph.D., Director of the Genetic and Metabolic Disease Program at the Children’s Research Institute at UT Southwestern, have identified new therapeutic targets for a significant percentage of patients who have the most common form of lung cancer among smokers, non-smokers and people under age 45. The targets were detected in spite of the myriad difficulties posed by genetically complex tumor lesions that have hindered efforts to identify therapeutic opportunities. Read the research published in Cell.
Sept. 3, 2013 — Glutamine is an abundant and highly versatile nutrient whose metabolism has implications for tumor cell biology, making it an appealing target for new clinical strategies to detect, monitor and treat cancer. Ralph DeBerardinis, M.D., Ph.D., Director of the Genetic and Metabolic Disease Program at the Children’s Research Institute at UT Southwestern (CRI); Ajla Wasti, M.D., a clinical fellow at CRI; and Chris Hensley, an M.D./Ph.D. student at CRI, have evaluated the metabolic functions of glutamine and its involvement in supporting tumor malignancy, in an effort to better understand how the information could be used in clinical oncology. Read their research review published in The Journal of Clinical Investigation.
Aug. 1, 2013 — An international team of researchers including Ralph DeBerardinis, M.D., Ph.D., Director of the Genetic and Metabolic Disease Program at the Children’s Research Institute at UT Southwestern, have found that the formation of new blood vessels is not only directed by genetic signals, but also by metabolism of glucose. The discovery opens up new opportunities to manipulate glucose metabolism to combat tumors and other diseases characterized by the formation of abnormal blood vessels. Read the research published in Cell.
July 25, 2013 — Researchers including Ralph DeBerardinis, M.D., Ph.D., Director of the Genetic and Metabolic Disease Program at the Children’s Research Institute at UT Southwestern, have discovered a metabolic activity that influences malignancy in renal cancer cells lacking the metabolic enzyme fumarate hydratase. In these cells, excess fumarate binds to the natural antioxidant glutathione, leaving the cell exposed to high levels of reactive oxygen species that reprogram gene expression. The discovery may help explain the puzzle of why some cancer cells contain excess fumarate, and suggest new ways to treat these cancers. Read the research published in Molecular Cell.
April 19, 2013 — Ralph DeBerardinis, M.D., Ph.D., Assistant Professor of Pediatrics and Genetics at the Children’s Research Institute at UT Southwestern, has been elected a member of the American Society for Clinical Investigation (ASCI). Founded in 1908, ASCI is one of the country’s most respected medical honor societies, with more than 3,000 physician-scientists from all medical specialties who have been elected to the society for their outstanding achievements in biomedical research. More information about ASCI is available here.
April 2, 2013 — Ralph DeBerardinis, M.D., Ph.D., and Hao Zhu, M.D., are the first two faculty members recruited to join Sean Morrison, Ph.D., at Children’s Medical Center Research Institute at UT Southwestern (CRI). Dr. DeBerardinis, whose lab focuses on cancer and metabolism, and Dr. Zhu, whose lab focuses on liver cancer, recently discussed their reasons for joining CRI and what each hopes to achieve through their research in the coming years. Read the Q&A.
Nov. 26, 2012 — Ralph DeBerardinis, M.D., Ph.D., Assistant Professor of Pediatrics and a faculty member at the Children’s Research Institute, shares how an award from the Cancer Prevention Research Institute of Texas (CPRIT) has led to the discovery of unique metabolic pathways that enable tumor growth. Watch the video.