TMC PULSE

t m c » p u l s e | o c t o b e r 2 0 1 8 35 physiologist who won a Nobel Prize in 1931 for his work investigating the metabolism of tumors and the respiration of cancer cells. He is the namesake of two observa- tions in bio- chemistry: a pathway in plant physiology and another pathway in oncology. Warburg hypothesized that cancer growth stemmed from tumor cells gener- ating energy—called adenosine triphosphate, or ATP—through the anaerobic breakdown of glucose, known as fermentation. This is in contrast to normal cells, which get energy from converted glucose called pyruvate in a process known as glycolysis. In a biographical sketch of Warburg chronicled by the National Institutes of Health, Warburg said this about his hypothesis during a 1966 lecture: "Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause … the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar." By activating SRC-3, the Warburg pathway unleashes one of the most potent oncogenes respon- sible for the spread of breast and other cancers. "It is the second-most expressed oncogene in all of the human can- cers," O'Malley said. "Normally, it plays a nice little function to keep the cell going, but when it gets over-activated, the cancer cell uses it to drive all of the processes for cell division and replication." This happens when the sugar activates the PFKFB4 enzyme, which then phosphorylates the SRC-3 oncogene, making it go from inactive to active and stimulating all the genes to grow the cancer. Generating cell energy Though some cells choose the Warburg pathway to make ATP, it is not the only way normal cells produce energy from glucose. The other way takes place in the mitochon- dria—the powerhouse of the cell— which yields significantly more energy than the Warburg path- way, explained O'Malley, who also served as Baylor's Thomas C. Thompson Chair in Cell Biology and associate director of basic research in the Dan L Duncan Comprehensive Cancer Center. Still, about 80 percent of cancer cells switch to the Warburg path- way, preferring to generate ATP via fermentation, he noted. "Cancer cells need a lot of energy, so people have wondered why the cancer cells do this," O'Malley said. "They have hypoth- esized that this pathway must provide other things the cancer cells want. That is the mystery we shed new light on with our study—that the Warburg is also activating the SRC-3 oncogene that drives the cancer cell to grow." The findings appear in a paper in the April 12, 2018 issue of the journal Nature. Subhamoy Dasgupta, Ph.D., the first author on the study, is an assistant professor of oncology at Roswell Park who completed his post-doctoral fellowship in O'Malley's lab at Baylor. Removing PFKFB4 or SRC-3 from the tumors suppresses breast tumor growth in the study's mice model, Dasgupta explained in the abstract. With that knowledge, the research group is working on thera- pies to directly target SRC-3, includ- ing developing drugs that bind to the protein and inactivate it. Team members are studying the effects of these drugs on breast cancer in animal models and could be ready to do a Phase 1 clinical trial in humans as early as next year. Struggling? We can help. 2001 Ladbrook Drive, Kingwood, TX 77339 With limited exceptions, physicians are not employees or agents of this hospital. For language assistance, disability accommodations and the non-discrimination notice, visit our website. 183430 n Inpatient psychiatric services for ages 5 and up n Day therapy program for teens ages 13-17 and adults n Inpatient detox and rehab for ages 18 and up n Evening addiction intensive outpatient for adults No-cost assessments 24 hours per day, 7 days a week. To learn more, visit kingwoodpines.com or call 281-957-2770. Yosef Gilad, Ph.D., left, a postdoctoral associ- ate in Baylor's Department of Molecular and Cellular Biology, works with O'Malley.

• Cover