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

Abstract

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.

MicroRNA-185 suppresses growth and invasion of colon cancer cells through inhibition of the hypoxia-inducible factor-2α pathway in vitro and in vivo

“…HIF-2α promotes hypoxic tumor cell proliferation by enhancing c-myc transcriptional activity (22) and results in CRC progression by dysregulating iron homeostasis (23). Disruption of the HIF-2α gene inhibits tumor angiogenesis and perfusion in human colon cancer cells (24). In the present study, overexpression of miR-185 suppressed proliferation and invasion, and reduced expression levels of HIF-2α in colon cancer cells, suggesting that miR-185 may be implicated in the development of colon cancer cells through inhibition of the HIF-2α pathway.…”

MicroRNAs Regulation of Tumor Angiogenesis

“…HIF-3 lacks structures for transactivation existed in the C-termini of HIF-1 and HIF-2 . HIF-2 might contribute to tumor angiogenesis in some cells (Burkitt et al, 2009;Favier et al, 2007;Giatromanolaki et al, 2006). However regulation of HIF-2 or HIF-3 by miRNAs has not reported yet.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…123 Burkitt et al at the University of Michigan Comprehensive Cancer Center demonstrated that genetic disruption of both HIF-1a and HIF-2a had synergistic anti-tumour activity when combined with sunitinib in a colorectal xenograft model. 124 Clinically, Kummar et al at the NCI demonstrated that metronomic dosing of TPT inhibited HIF-1a in patients, and that correlated with antiangiogenics as well, as measured by decreased tumour expression of VEGF and decreased tumour blood flow and permeability. These data validate extensive preclinical data showing that metronomic TOP1 inhibition can inhibit HIF-1a and important downstream targets of HIF-1.…”