June 25, 2021
UNC Eshelman School of Pharmacy Associate Professor Qisheng Zhang, Ph.D., recently was awarded a $2,247,857 grant from the National Cancer Institute to study mutations in lymphomas and leukemias with the goal of identifying new therapeutics.
The four-year grant will support his work, “A high-throughput platform to identify selective allosteric inhibitors of the PLC-g isozymes.” Co-PIs on the study include John Sondek, Ph.D., and Kenneth Pearce, Jr., Ph.D.
Together, the team will study two phospholipase C gamma (PLC-g1 and PLC-g2) proteins that are frequently mutated in lymphomas and leukemias. Remarkably, PLC-g1 is the most frequently mutated protein – occurring about 37% of the time – in patients with adult T-cell leukemia/lymphoma.
“All mutants have increased phospholipase activity, so by inhibiting aberrantly active PLC-g1 we may have a new approach to reduce tumor growth,” Zhang said.
Similarly, mutated forms of PLC-g2 arise in response to treatment of B-cell leukemias and lead to refractory disease, meaning a cancer has stopped responding to treatment.
Zhang and coworkers previously developed unique fluorescent substrates WH-15 and XY-69 that selectively monitor the catalytic activity of PLC isozymes in real-time. In this project, the team will use these substrates and developed assays to conduct high-throughput screens that will identify compounds that selectively inhibit the two PLC-g isozymes.
“Our goal is to discover selective inhibitors to further understand how hyperactive PLC-g proteins drive cancer and ultimately to develop novel approaches to treat leukemias and lymphomas,” Zhang said.