Targeting cancer with tumor-specific therapeutic strategies—metabolic reprogramming beyond the Warburg effect

Although metabolic reprogramming has only recently been characterized as an emerging hallmark of cancer (1), that cancer cells utilize nutrients differently than non-malignant cells is a principle that was observed almost a century ago. In the 1920’s, Otto Warburg identified that tumors demonstrated increased glycolytic flux relative to adjacent normal tissues and had an increased reliance on glycolysis relative to oxidative phosphorylation for ATP production (2). He found that even in aerobic conditions, cancer cells preferentially utilized glycolysis despite its inefficiencies. Thus, the concept of targeting a tumor cell’s source of nutrition as an anti-cancer strategy became a viable approach. We have selectively targeted colon cancer cells by exploiting their propensity for increased glycolytic flux using a non-metabolizable glucose analog to enhance sensitivity to TRAIL-induced apoptosis (3).