Abstract

Cells can respond to low oxygen tension, or hypoxia by increasing oxygen delivery or adapting to decreased oxygen availability. An essential regulator of oxygen homeostasis is the transcription factor, hypoxia-inducible factor-1 (HIF-1). HIF-1 exquisitely regulates a variety of processes to respond to hypoxia and is itself exquisitely regulated to prevent an inappropriate hypoxic response. The objective of this proposal is to determine the role of HIF-1 in the development and progression of cancer, ultimately to determine whether HIF-1 and its downstream targets are good candidates for rational drug design or whether they can be used as diagnostic or prognostic markers. Achieving this goal requires a biochemical and cellular understanding of the dynamic relationship between HIF-1 and its negative regulators, the prolyl hydroxylase enzymes. How these prolyl hydroxylases contribute to the regulation of HIF-1 and thus the development or progression of cancer is poorly understood. Genetic systems to knockdown the function of these enzymes will be instrumental in understanding the contribution of these enzymes to tumorigenesis. ? ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA123823-03
Application #
7473960
Study Section
Special Emphasis Panel (ZRG1-F09-S (20))
Program Officer
Jakowlew, Sonia B
Project Start
2006-08-03
Project End
2009-08-02
Budget Start
2008-08-03
Budget End
2009-08-02
Support Year
3
Fiscal Year
2008
Total Cost
$52,048
Indirect Cost

  Institution

Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Bonnet, Muriel; Flanagan, Jack U; Chan, Denise A et al. (2014) Identifying novel targets in renal cell carcinoma: design and synthesis of affinity chromatography reagents. Bioorg Med Chem 22:711-20
Chan, Denise A; Sutphin, Patrick D; Nguyen, Phuong et al. (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3:94ra70
Bonnet, Muriel; Flanagan, Jack U; Chan, Denise A et al. (2011) SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells. Bioorg Med Chem 19:3347-56
Chan, Denise A; Giaccia, Amato J (2011) Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov 10:351-64
Chan, D A; Giaccia, A J (2010) PHD2 in tumour angiogenesis. Br J Cancer 103:1-5
Hay, Michael P; Turcotte, Sandra; Flanagan, Jack U et al. (2010) 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death. J Med Chem 53:787-97
Chan, Denise A; Kawahara, Tiara L A; Sutphin, Patrick D et al. (2009) Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 15:527-38
Choi, Clara Y H; Chan, Denise A; Paulmurugan, Ramasamy et al. (2008) Molecular imaging of hypoxia-inducible factor 1 alpha and von Hippel-Lindau interaction in mice. Mol Imaging 7:139-46
Turcotte, Sandra; Chan, Denise A; Sutphin, Patrick D et al. (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14:90-102
Chan, Denise A; Giaccia, Amato J (2008) Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics. Cell Cycle 7:2987-90

Showing the most recent 10 out of 13 publications