Chemical metabolic inhibitors for the treatment of blood-borne cancers

Abstract

Tumor cells, including leukemic cells, remodel their bioenergetic system in favor of aerobic glycolysis. This process is called "the Warburg effect" and offers an attractive pharmacological target to preferentially eliminate malignant cells. In addition, recent results show that metabolic changes can be linked to tumor immune evasion. Mouse models demonstrate the importance of this metabolic remodeling in leukemogenesis. Some leukemias, although treatable, remain incurable and resistance to chemotherapy produces an elevated percentage of relapse in most leukemia cases. Several groups have targeted the specific metabolism of leukemia cells in preclinical and clinical studies to improve the prognosis of these patients, i.e. using L-asparaginase to treat pediatric acute lymphocytic leukemia (ALL). Additional metabolic drugs that are currently being used to treat other diseases or tumors could also be exploited for leukemia, based on preclinical studies. Finally, we discuss the potential use of several metabolic drugs in combination therapies, including immunomodulatory drugs (IMiDs) or immune cell-based therapies, to increase their efficacy and reduce side effects in the treatment of hematological cancers.

Figure 1. Co-regulation of metabolism and immune function to kill tumor cells

Metabolic drugs such as DCA and Metformin induce OXPHOS that up-regulate the MHC-I expression, immunomodulators (IMiDs) and IL-2 stimulate the anti-tumor activity of effector immune cells (CTL and NK cells). This strategy will help the CTLs to recognize and bind to the MHC-I complex. In contrast, inhibition of OXPHOS reduces MHC-I expression and Natural Killer cells (NK) will recognize the absence of MHC-I and the stress signals. GLS inhibitors could induced NK activation by these means.