Many cancer patients initially respond well to surgery followed by chemo and radiation therapies. Long-term relapse, however, is a common occurrence that is attributed to the survival of a small subset of cancer cells following initial treatment. These cells share a number of features with stem cells and have therefore been called cancer stem cells. These cells exhibit high levels of sphere-forming and tumor-initiating capability, metastatic aptitude, ability to differentiate into multiple lineages of cells, and the ability to transition between quiescent and proliferative states enabling them to repopulate the tumor. Early studies indicated that cancer stem cells pursue glycolysis for ATP generation like their epithelial counterparts. More recently, however, a number of studies reveal that cancer stem cells utilize mitochondrial biogenesis and predominantly pursue oxidative phosphorylation as their energy source. Hence, metabolic plasticity is emerging as a critical aspect of cancer stem cell metabolism that can be therapeutically targeted.
Our lab has developed potent inhibitors of monocarboxylate transporters 1/4 (MCTs 1/4) and mitochondrial pyruvate carrier 1 and 2 (MPC 1/2). By inhibiting these transporters, we have shown the inhibition of metabolic plasticity in tumors and an efficient anticancer efficacy in various tumor models in mice.