Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment

Sunitinib is an oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has recently been shown to have clinical benefit as a single agent in renal cell cancer and gastrointestinal stromal tumors, leading to its Food and Drug Administration approval for treatment of these cancers. However, the benefit is short-lived; and for the majority of cancers, sunitinib single-agent clinical activity is low. Therefore, combination strategies with sunitinib are currently in clinical development. The hypoxia-inducible transcription factors, HIF-1 and HIF-2, induce gene programs important for cancer cell growth and angiogenesis. We hypothesized that inhibiting HIF-1 and HIF-2 would further improve tumor response to sunitinib therapy. To test this hypothesis, HIF-1 alpha and HIF-2 alpha genes were disrupted in colon cancer cells. We found that disruption of HIF-1 alpha, HIF-2 alpha, or both HIF-1 alpha and HIF-2 alpha genes led to improved tumor response to sunitinib. For xenografts in which both HIF-1 alpha and HIF-2 alpha genes were disrupted, there was prolonged complete remission with sunitinib treatment in 50% of mice. This enhanced response was mediated by two potential mechanisms. First, tumor angiogenesis and perfusion were almost completely inhibited by sunitinib when both HIF-1 alpha and HIF-2 alpha genes were disrupted. The enhanced inhibitory effect on tumor angiogenesis was mediated by the inhibition of multiple proangiogenic factors, including vascular endothelial growth factor and angiopoietin-like protein 4, and the induction of the antiangiogenic factor, thrombospondin 1. Second, disruption of HIF-1 alpha, HIF-2 alpha, or both HIF-1 alpha and HIF-2 alpha genes directly inhibited tumor cell proliferation. These preclinical findings have clinical implications and suggest novel clinical trials. [Mol Cancer Ther 2009;8(5):1148-56]