Dual inhibition of glycolysis and oxidative phosphorylation in cancer: can active targeting improve efficacy and safety?

Several inhibitors of glycolytic and oxidative metabolism have advanced into clinical trials but the results obtained so far have been disappointing for two main reasons: lack of efficacy and toxicity. Moreover, inhibition of one of the two pathways has always been shown to lead to the compensatory upregulation of the other pathway. This has led to test inhibitors of the two pathways in combination. Preclinical studies have yielded encouraging results but the side effect profile of these combinations appears to have worsened compared to individual compounds. This has suggested the possibility to test these combinations upon loading them on carrier molecules that locate preferentially to the tumor microenvironment through the enhanced permeability and retention effect or specifically to tumor cells by means of targeting molecules displayed on the carriers. Very little information is available for this approach and only with nanoparticulates as carriers of the inhibitors. No information is available about inhibitors of the two pathways conjugated to targeting moieties, whether antibodies or small molecules, while this approach has been, so far, the most successful in achieving targeted drug delivery to tumors. We suggest that these targeting approaches, i.e. nanoparticles carrying inhibitors or targeting molecules bearing conjugated inhibitors should be investigated more deeply because they hold promise to abrogate energy production specifically in tumor cells, thereby offering the possibility to have available a new class of molecules to act on tumor cells, whether quiescent or proliferating, and whether in early or late steps of tumorigenesis.