Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand

Abstract

Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Its presence has been established to be a poor prognostic factor in multiple cancer types, and past hypoxia-directed approaches have yielded generally disappointing results. Previous approaches have centered on either increasing oxygen delivery or administering agents that preferentially radiosensitize or kill hypoxic cells. However, a novel and potentially more effective method may be to increase therapeutic benefit by decreasing tumor oxygen consumption via agents such as metformin or nelfinavir in a patient population that is enriched for tumor hypoxia. This promising approach is currently being investigated in clinical trials and the subject of this article.

Figure 1

The role of oxygen in radiation-induced DNA damage and agents that can reduce cellular oxygen consumption. Oxygen is required to elicit maximal DNA damage following ionizing radiation (primarily double strand breaks) through the generation of oxidative free radicals. Hence, hypoxic tumors are relatively resistant to cell killing in response to radiation. Drugs such as metformin and arsenic trioxide have been shown to reduce oxygen consumption, likely by inhibiting electron transport chain function. Inhibitors of the PI3K/AKT/mTOR signaling pathway have also been shown to decrease oxygen consumption, possibly by inhibiting the pyruvate dehydrogenase (PDH) complex. These drugs could be used to reduce tumor oxygen consumption and tumor hypoxia, thus potentially increasing radiosensitization.