Cancer development relies on the dynamic balance between cancer epithelial cells and the tumor vasculature. Thus, antiangiogenic therapy is a rational and effective approach against tumor growth and progression. Vascular endothelial growth factor A (VEGFA or VEGF) is a well-proven dominant growth factor in tumor angiogenesis, which has been further substantiated by the clinical promise of targeting VEGF in the treatment of human cancers. The HIF-1 transcription factor complex (HIF-1a/HIF-1B) plays an essential role in the response of cancer cells to hypoxia. Extensive evidence shows that HIF-1 induces the expression of genes important in hypoxia response such as anti-apoptosis, glycolysis, angiogenesis, cell migration, and metastasis. However, it remains unclear whether HIF-1a solely mediates tumor survival under hypoxia; or whether redundant pathways contribute to mechanisms of survival. For example, the HIF-2 complex (HIF-2a/HIF-1B) may also regulate genes important in hypoxia response. A growing concern with effective antiangiogenic therapy is tumor reactive resistance: The resulting increase in intratumoral hypoxia may drive the selection of cells that are less dependent on the vasculature, cells which in turn may be more malignant. While reactive resistance is thought to be driven by hypoxia, it remains to be determined whether reactive resistance is mediated by HIFs (HIF-1a and HIF-2B). The primary aim of this proposal is to determine the direct role of HIF-1a in mediating tumor response to antiangiogenic therapy. The secondary aim is to distinguish the roles of HIF-1a and HIF-2B in tumor response to hypoxic stress. To directly investigate these aims, a pre-clinical model system, using human cancer cell knockout technology, was developed. The insights gained from these studies should contribute to our understanding of cancer biology and the rational combination of antiangiogenic therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
1K22CA111897-01A1
Application #
6968658
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$158,500
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wenger, Justin B; Santos, Napoleon; Liu, Yanxia et al. (2011) Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma? Oncol Rev 5:177-184
Santos, Napoleon; Wenger, Justin B; Havre, Pamela et al. (2011) Combination therapy for renal cell cancer: what are possible options? Oncology 81:220-9
Wenger, Justin B; Chun, Sang Y; Dang, Duyen T et al. (2011) Combination therapy targeting cancer metabolism. Med Hypotheses 76:169-72
Chun, Sang Y; Johnson, Craig; Washburn, Joseph G et al. (2010) Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1? and HIF-2? target genes. Mol Cancer 9:293
Burkitt, Kyunghee; Chun, Sang Y; Dang, Duyen T et al. (2009) Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment. Mol Cancer Ther 8:1148-56
Dang, Duyen T; Chun, Sang Y; Burkitt, Kyunghee et al. (2008) Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res 68:1872-80
Chun, S Y; Chen, F; Washburn, J G et al. (2007) CDX2 promotes anchorage-independent growth by transcriptional repression of IGFBP-3. Oncogene 26:4725-9
Dang, Duyen T; Chen, Fang; Gardner, Lawrence B et al. (2006) Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res 66:1684-936