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-1α and HIF-2α genes were disrupted in colon cancer cells. We found that disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes led to improved tumor response to sunitinib. For xenografts in which both HIF-1α and HIF-2α 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-1α and HIF-2α 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-1α, HIF-2α, or both HIF-1α and HIF-2α genes directly inhibited tumor cell proliferation. These preclinical findings have clinical implications and suggest novel clinical trials.
Burkitt
Kyunghee
K
Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Chun
Sang Y
SY
Dang
Duyen T
DT
Dang
Long H
LH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human