Defects in proteins that turn genes on and off are involved in the development of many cancers. Researchers are seeking to develop precision chemotherapy drugs to repair these defective proteins as a new way to stop cancer.
One of these researchers is quantitative biologist H. Courtney Hodges, who was recruited in 2017 to Baylor College of Medicine and MD Anderson Center for Cancer Epigenetics, with the help of a First-Time Tenure-Track Award from CPRIT. He was most recently a postdoctoral fellow in pathology and developmental biology at Stanford University School of Medicine.
Hodges studies a protein inside cells, called BAF, that is responsible for turning genes on and off. Every cell in the human body has the same DNA, but the pattern of gene expression facilitated by this protein complex is what distinguishes a liver cell from a skin cell or neuron. In about 20 percent of cancers, this protein is altered, and gene control is scrambled.
One of the cancers that Hodges focuses on is a rare but deadly kidney tumor that only occurs in people with sickle-cell trait — an inherited disorder that causes hemoglobin to be irregularly shaped. Patients are typically young African-Americans in their teens or 20s. The cancer is very aggressive, often metastatic at the time it’s diagnosed, and can lead to death within six months. It’s resistant to both standard chemotherapy and immunotherapy.
In this cancer, renal medullary carcinoma, the BAF complex has lost a specific piece, which leads to out-of-control growth of kidney cells. When the BAF protein is functioning normally, it turns genes off. But when the defective form takes over it shuts down the mechanism that stops cells from proliferating. “It’s like cutting the brake line on a car, so it can never stop,” Hodges says. “The engine keeps running.”
Hodges is using microscopy to watch in real time how this protein functions inside cells, and see how the defect affects the physical function of the protein complex. He’s hoping to use this to screen for chemical compounds that might treat disease by repairing certain aspects of BAF’s activity.
“We’d like to see how we could restore the function of this complex,” Hodges says. “Understanding the real vulnerabilities of this cancer will help develop new treatment opportunities.”
What Hodges learns from studying this defective BAF complex could also help in the treatment of other cancers. A kidney cancer that occurs in young children also involves the loss of the same piece of the protein complex in a different context. He’s studying two other childhood cancers, leukemia and neuroblastoma, that are dependent on BAF in different ways. “It’s a key player in many cancers, so we know it’s the right one to focus on,” he says.
Hodges finds the scientific environment at the Texas Medical Center very stimulating. “I can’t think of any other place that has the density — and talent — of people interested in these problems,” he says.
He grew up in Dallas, although he never envisioned himself coming back to Texas. But the CPRIT award allows him the freedom to do ambitious projects that he wouldn’t have been able to do anywhere else. “The funds provided by CPRIT were the most exciting aspect of coming back to Texas,” he says.
He’s received additional funding for his research from both the Gabrielle’s Angel Foundation and the V Foundation for his work on aggressive childhood leukemia and high-risk neuroblastoma.
Hodges studied biochemistry and mathematics, graduating with honors, at Texas A&M University, and completed his Ph.D. in biophysics at the University of California at Berkeley. He was a postdoctoral fellow at Stanford for 7 years before returning to Texas.
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