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Early in the 20th century, the German scientist Otto Warburg observed that cancer cells produce energy differently than normal cells do. Cancer cells break down glucose (the simplest form of sugar) at a high rate, while normal cells use the energy from glucose at a relatively low rate. The pathways through which energy is processed in cancer and normal cells are completely different, too. Warburg won a Nobel Prize in Physiology in 1931 for his work, and his observations about metabolism in cancer cells—called the Warburg effect—are fundamental to cancer research even today.
Through the decades that followed, researchers made a long string of discoveries related to the Warburg effect:
- Transcription factors, which are proteins that bind to specific sequences of DNA, regulate cell functions.
- Some transcription factors called hypoxia-inducible factors (HIFs) control both red blood cell production and the way cells produce energy.
- High levels of HIFs in cancer cells are responsible for their unique way of generating energy.
- There are gene mutations of the HIF pathway in a non-cancerous disease called polycythemia that causes the body to overproduce red blood cells.
But HIF-producing mutations were never found in cancer cells. Until now.
A team led by Huntsman Cancer Institute (HCI) investigator Josef Prchal, MD, professor in the Division of Hematology and Hematologic Malignancies at the University of Utah, used genomic sequencing techniques to survey key portions of the human genome. They found a mutation of the transcription factor HIF2α in tumor cells of two patients with rare cancers—paraganglioma-pheochromocytoma (a neuroendocrine cancer with tumors in various body parts including the adrenal glands) and somatostatinoma (an endocrine cancer of the pancreas). The mutation had never before been identified in non-inherited cancers. Prchal’s research results appeared in The New England Journal of Medicine in September 2012.
These findings mark the beginning of a new trail of cancer discovery. “Learning whether HIF pathway mutations are present in other cancers could increase our understanding of cancer cell metabolism,” says Prchal. “It also offers a possible new target for cancer treatments.”