Combination Strategies Targeting Hypoxia Inducible Factor 1 (HIF-1) for Cancer Therapy

Abstract

Solid tumors often present regions of decreased oxygen levels (hypoxia) due to an imbalance between increased oxygen consumption and insufficient oxygen delivery from the aberrant tumor vasculature. Intratumor hypoxia is associated with altered cellular metabolism, an invasive and metastatic phenotype, as well as resistance to radiation and chemotherapy. The discovery of Hypoxia Inducible Factor-1 (HIF-1), a transcription factor critically involved in cellular responses to hypoxia and tumor progression, has provided evidence of a potential molecular target of intratumor hypoxia that could be exploited for the development of novel cancer therapeutics. A growing number of small molecule inhibitors of HIF-1, which act by distinct molecular mechanisms, have been described so far. However, HIF-1 expression in human cancers is focal and heterogeneous, consistent with the possibility that single agent HIF-1 inhibitors may have limited clinical activity. It is then plausible that combination strategies aimed at maximizing the clinical potential of HIF-1 inhibition may be more effective.