2018 LCRF Scientific Grant Program
Xiaochao Tan, PhD
The University of Texas MD Anderson Cancer Center
Targeting chromosome 1q21.3-amplified lung cancer using PI4KB antagonists
Lung cancer cells secrete proteins that maintain their survival and enhance their metastatic activity. Clinical trials designed to inhibit secretion by utilizing neutralizing antibodies or decoy receptors against secreted proteins have been largely unsuccessful, which is not surprising given the functional redundancy of secreted protein networks. Addressing this issue will require the identification of actionable targets positioned proximally within the secretory pathway. In work funded by the Lung Cancer Research Foundation, Dr. Tan has shown that secretion is pharmacologically actionable at the level of the Golgi apparatus, an intracellular organelle that sorts, packages, and ships proteins to the cell membrane for secretion into the extracellular space. Her group will test the anti-tumor activity of drugs that inhibit PI4KIIIβ, an enzyme that drives protein packaging in the Golgi. These drugs are currently being developed as anti-viral agents for individuals infected with deadly viruses such as hepatitis and Ebola virus. On the basis of their finding that PI4KIIIβ inhibitors preferentially kill lung cancer cells with a specific genetic mutation, they will test PI4KIIIβ inhibitors in mice bearing lung cancers with that mutation and see whether the drugs are safe to administer and cause tumor regression. If they do, these findings will provide a foundation for clinical trials utilizing PI4KIIIβ inhibitors to inhibit secretion in lung cancer.