As they grow, cells buried in the center of a solid tumor outstrip the available oxygen supply. But rather than dying, these cells thrive under low-oxygen conditions. This superpower enables some cancer cells to survive treatments designed to kill them.
But their survival under hypoxic conditions may prove an Achilles heel if biochemist Qing Zhang can figure out the genes and enzymes that grant these cells immortality.
Zhang was recruited in 2019 to the University of Texas Southwestern Medical Center Department of pathology. He was associate professor at Lineberger Comprehensive Cancer Center at the University of North Carolina School of Medicine, and was recruited with the help of a Rising Star award from CPRIT.
As a tumor grows, it begins as a single cell and multiplies to form a larger tumor that can be thought of as a ball shape. Blood vessels can only supply the surface of the ball, so the center becomes more and more deprived of oxygen.
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As they grow, cells buried in the center of a solid tumor outstrip the available oxygen supply. But rather than dying, these cells thrive under low-oxygen conditions. This superpower enables some cancer cells to survive treatments designed to kill them.
But their survival under hypoxic conditions may prove an Achilles heel if biochemist Qing Zhang can figure out the genes and enzymes that grant these cells immortality.
Zhang was recruited in 2019 to the University of Texas Southwestern Medical Center Department of pathology. He was associate professor at Lineberger Comprehensive Cancer Center at the University of North Carolina School of Medicine, and was recruited with the help of a Rising Star award from CPRIT.
As a tumor grows, it begins as a single cell and multiplies to form a larger tumor that can be thought of as a ball shape. Blood vessels can only supply the surface of the ball, so the center becomes more and more deprived of oxygen.
"In normal circumstances, you would think those interior cells would die," Zhang explains, "but on the contrary, they thrive, so what doesn’t kill them actually makes them stronger."
Zhang is studying two solid tumors, kidney cancer and breast cancer, to find the pathways that sense oxygen levels. These oxygen-sensing mechanisms alter gene expression and metabolism inside the cells, enabling them to survive under extremely harsh conditions.
Identifying the key elements of the oxygen-sensing pathway would allow Zhang to potentially find new targets for cancer therapeutics. In breast cancer, in particular, he is studying an enzyme called EgIN2, which contributes to several different subtypes of breast cancer, including the most intractable, triple-negative breast cancer. He’s developing EgIN2 inhibitors and studying their anti-tumor properties in cell lines and mice.
Zhang recently identified another gene in triple-negative breast cancer, BBOX1, which when silenced caused tumors to shrink in mice. A drug currently prescribed to treat coronary artery disease seems to inhibit the BBOX1 enzyme and shows potential as a cancer therapeutic agent.
In kidney cancer, he’s focusing on a gene called VHL, the most prominent tumor suppressor, mutated in 70-80% of patients. He’s screening the genome to identify VHL-related downstream events that could be targeted by therapeutics. He has identified one potential therapy called SPHK inhibitor, which has shown some success so far in preventing tumors from growing in mice. The hope is to find a therapeutic that targets only cancerous cells with a VHL mutation and leaves normal cells unscathed.
Even though Zhang’s research focuses on these two cancers, he says his findings will be applicable to many other solid-tumor cancers, because most of them also experience low-oxygen conditions. "We use this model system to identify therapeutic targets, and develop efficient and potent inhibitors that would be applicable for many other cancers," he says.
Zhang says funding from CPRIT has been crucial for his work, given the uncertainty of federal funding. "Honestly without this kind of support we would not be able to pursue these risky ideas, even though they are potentially high-reward," he says. He credits the research environment at UT Southwestern, saying that collaborations, building infrastructure, and a culture of research excellence help support his research.
Zhang received his undergraduate training in biochemistry from Wuhan University in China, and his Ph.D. in pharmacology from the University of Pittsburgh School of Medicine. He was a research fellow and instructor at Dana Farber Cancer Institute before taking a position in 2013 as an assistant professor of pathology and laboratory medicine at UNC Chapel Hill. He was promoted to associate professor in 2019.
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