Metabolic Control and Anticancer Mechanism

ABSTRACT As a central controller of cancer growth and metabolism, mTORC1 pathway is commonly mutated and activated in human cancer, leading to uncontrolled growth. Cancer cells are ‘addicted’ to elevated mTORC1 signaling, rendering mTORC1 a desirable cancer drug target. The highly specific mTORC1 inhibitors rapamycin analogs

(rapalogs, e.g. temsirolimus) are US FDA-approved oncology drugs. However, their clinical response has been moderate, which is in a large part due to incomplete understanding of mTORC1 signaling mechanisms underpinning rapamycin action. In this application, we will test the central hypothesis that nuclear mTORC1

signaling promotes aerobic glycolysis, or Warburg Effect, through a long non-coding RNA (lncRNA) NEAT1- dependent mechanism, which is important for mTORC1-driven tumorigenesis and rapamycin response. A successful completion of this project will provide a deeper understanding of this oncogenic pathway and

therapeutic response to its blockage.