Finally a potentially effective therapeutic
Finally, a potentially effective therapeutic approach is to target the LDH enzymes that mediate bidirectional conversion of pyruvate into lactate. In particular, because LDHA is the predominant isoform expressed in glycolytic tumours, an array of LDHA-targeting compounds have been proposed and validated in preclinical models . Among these, gossypol (AT-101) and its derivative FX-11, galloflavin, and N-hydroxyindole-based compounds have been shown to inhibit preferentially the LDHA isoforms, with the exception of AT-101 which shows comparable Ki values for LDHA and LDHB . Importantly, other inhibitors have been recently developed as potential anticancer therapeutic agents , although further validation is required. Although LDHA targeting has not been reported to be toxic, a limitation of this approach could emerge from differential LDH isoform expression that has been described in different tumours . Indeed, LDHB is expressed in several tumour types 79, 80 and, importantly, because metabolic reprogramming has been reported to play a role in tumourigenesis and therapy TH287 australia , a switch in LDH isoform expression may occur during tumour progression and could be influenced by therapeutic intervention. Therefore, the efficacy of LDH inhibitors will depend on the isoforms expressed and will be context (cancer and metabolic)-dependent. Importantly, to improve the efficacy of LDH targeting, it would be tempting to combine LDHA inhibitors with biguanides (i.e., metformin or phenformin) that, used as mitochondrial blockers, force a reliance on glycolysis, an effective therapeutic approach in an experimental model of melanoma . Although metabolic targeting approaches have proved to be efficient in the preclinical setting, to date their translational impact remains limited. A potential issue that complicates this translation may be the metabolic heterogeneity of the cell populations that compose the tumour mass, as described in the current review. Indeed, targeting lactate usage will be effective in lactate-exploiting cells but will be ineffective on Warburg- or glutamine-dependent cells, hence the selectivity of metabolic targeting will be dependent on the metabolic demands of each cellular subpopulation. Different metabolic behaviours generally occur also between the cancer cells that compose the same tumour (e.g., hypoxic vs. non-hypoxic regions, low- vs. high-nutrient perfuse regions), and a particular scenario characterized by complex metabolic mosaicism (that is difficult to target by single-agent administration) is that of a highly stroma-infiltrated tumour mass. In such a situation, a potentially effective metabolic approach may be to target the metabolic symbiosis between cancer and stromal cells. This could be achieved by forcing a metabolic switch of the tumour-composing cells. For instance, antiangiogenic drugs may induce a more hypoxic TME, an established effector of Warburg-like metabolism, hence offering a series of potential metabolic vulnerabilities that could be targeted in a more homogenous metabolic-dependent context. A series of compounds, that have been reported to force a specific metabolic phenotype in tumour and stromal cells, may be therefore combined to generate doublet or triplet drug regimens, a hypothesis that could rapidly be validated in preclinical settings. However, the limitation of such an approach in the long term is the potential emergence of resistant clones that are much more difficult to target during relapse. Indeed, aggressive tumours are characterised by higher metabolic plasticity, another potential explanation for the failures of previous trials with antimetabolic drugs. Finally, another underestimated issue that metabolic targeting could face is the role of the immune system in anticancer drug responses. Immune system activation is paralleled by a profound change in metabolic behaviours of immune cells . For instance, lymphocyte activation is an essential step for their antitumour activity, a step that is characterised by Warburg-dependent metabolism. Therefore, if an antimetabolic compound impairs tumour cell growth, it could also inhibit the host antitumour immune response, hence giving contradictory results in general tumour management. This crucial point emerged, for instance, when a combination of autophagy inhibitors (as an antimetabolic compound) and antineoplastic drugs, that were effective in cellular and immunocompromised models, were administered to immunocompetent mice, and this might possibly explain the failure of clinical trials with compounds that block autophagy .