Developing the ideal targeted cancer therapeutic requires a detailed molecular understanding of the pathways involved. The ideal targeted therapy specifically eradicates tumor cells, while sparing the normal tissue. Because the rapid growth of cancer cells depends on their ability to maintain an abundant oxygen supply, this process provides an opportunity for developing targeted therapies. Research in my lab focuses on the complex tumor microenvironment, specifically how cells sense and respond to low oxygen conditions, or hypoxia. Hypoxia is both a hallmark of solid tumors and a predictor of poor prognosis. It is therefore an attractive target to exploit. Cells respond to hypoxia by increasing oxygen delivery or adapting to decreased oxygen availability. The hypoxic response is largely mediated by a family of transcription factors, the hypoxia-inducible factors (HIFs). The HIFs exquisitely regulates a variety of processes involved in oxygen homeostasis and are themselves tightly regulated by key upstream oxygen sensors, the prolyl hydroxylases, to prevent inappropriate hypoxic responses. My work has focused on understanding the key upstream oxygen sensors, the prolyl hydroxylases. Our broad goal is to dissect the molecular pathways regulating oxygen sensing with the ultimately leading to candidates for rational drug design based on HIF.
Awards & Honors
Recent Significant Publications
Anbalagan S, Pires IM, Blick C, Hill MA, Ferguson DJ, Chan DA, Hammond EM. Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy, Radiother Oncol. 2012 Jun;103(3):388-93.
Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi JT, Wu J, Solow-Cordero DE, Bonnet M, Flanagan JU, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality, Sci Transl Med. 2011 Aug 3;3(94):94ra70.
Bonnet M, Flanagan JU, Chan DA, Lai EW, Nguyen P, Giaccia AJ, Hay MP. 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. 2011 Jun 1;19(11):3347-56.
Chan DA, Giaccia AJ. Harnessing synthetic lethal interactions in anticancer drug discovery, Nat Rev Drug Discov. 2011 May;10(5):351-64.
Wiley M, Sweeney KR, Chan DA, Brown KM, McMurtrey C, Howard EW, Giaccia AJ, Blader IJ. Toxoplasma gondii activates hypoxia-inducible factor (HIF) by stabilizing the HIF-1alpha subunit via type I activin-like receptor kinase receptor signaling, J Biol Chem. 2010 Aug 27;285(35):26852-60.
Patten DA, Lafleur VN, Robitaille GA, Chan DA, Giaccia AJ, Richard DE. Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species, Mol Biol Cell. 2010 Sep 15;21(18):3247-57.
Chan DA, Giaccia AJ. PHD2 in tumour angiogenesis., Br J Cancer. 2010 Jun 29;103(1):1-5.
Hay MP, Turcotte S, Flanagan JU, Bonnet M, Chan DA, Sutphin PD, Nguyen P, Giaccia AJ, Denny WA.4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death, J Med Chem. 2010 Jan 28;53(2):787-97.
Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment, Cancer Cell. 2009 Jun 2;15(6):527-38.
Chang, EI, Bonillas, RG, El-Ftesi, S, Chang, EI, Ceradini, DJ, Vial, IN, Chan, DA, Michaels, J 5th, and Gurtner, GC. Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds, FASEB J. 23: 906-15, 2009.
Ghosh, AK, Shanafelt, TD, Cimmino, A, Taccioli, C, Volinia, S, Liu, CG, Calin, GA, Croce, C, Chan, DA, Giaccia, A, Secreto, C, Wellik, L, Lee, Y, Mukhopadhyay, D, and Kay, NE. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells, Blood. 113: 5568-74, 2009.
Chan, DA, Kawahara, TL, Sutphin, PD, Chang, HY, Chi, JT, and Giaccia, AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment, Cancer Cell. 15: 527-38, 2009.
Chan DA, Koong AC, and Giaccia AJ. Hypoxia-mediated signaling pathways. Handbook of Cell Signaling 2nd edition. Editors-in-Chief: Bradshaw RA and Dennis EA. Oxford: Academic Press, 2009.
Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, and Giaccia AJ. Regulation of the histone demethylase JMJD1A by HIF-1a enhances hypoxic gene expression and tumor growth. Mol Cell Biol. Oct 26; Epub., 2009.
Hay MP, Turcotte S, Flanagan JU, Bonnet M, Chan DA, Sutphin PD, Nguyen P, Giaccia AJ, and Denny WA. 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death. J Med Chem. Dec 8. Epub., 2009
Page, EL, Chan, DA, Giacci,a AJ, Levine, M, and Richard, DE. Hypoxia-inducible factor-1a stabilization in vascular smooth muscle cells through intracellular ascorbate depletion, Mol Biol Cell. 19: 86-94, 2008.
Choi, CYH, Chan, DA, Paulmurugan, R, Sutphin, PD, Le, QT, Koong, AC, Zundel, W, Gambhir, SS, and Giaccia, AJ. Molecular imaging of HIF-1alpha and VHL interaction in mice, Mol Imaging. 7: 139-46, 2008.
Lauzier MC, Robitaille GA, Chan DA, Giaccia AJ, and Richard DE. BiPS, a matrix metalloprotease inhibitor, is a novel and potent activator of hypoxia-inducible factors, Mol Pharmacol. 74: 282-8, 2008.
Huang, M, Chan, DA, Jia, F, Xie, X, Li, Z, Hoyt, G, Robbins, RC, Chen, X, Giaccia, AJ, and Wu, JC. Molecular imaging of RNA interference therapy targeting prolyl hydroxylase-2 for treatment of myocardial ischemia, Circulation. 118: S226-S233, 2008.
Turcotte, S, Chan, DA, Sutphin, PD, Hay, MP, Denny, WA, and Giaccia, AJ. A novel molecule targeting VHL-deficient renal cell carcinoma that induces autophagy cell death, Cancer Cell. 14: 90-102, 2008.
Pan, Y., Mansfield, KD, Bertozzi, CC, Rudenko, V, Chan, DA, Giaccia, AJ, and Simon, MC. Multiple factors affecting cellular redox status and energy metabolism modulate HIF prolyl hydroxylase activity in vivo and in vitro, Mol Cell Biol. 27: 912-25, 2007.
Sutphin, PD, Chan, DA, Li, JM, Turcotte, S, Krieg, AJ, and Giaccia AJ. Targeting the loss of the VHL tumor suppressor gene in renal cell carcinoma cells, Cancer Res. 67: 5896-905, 2007.
Cecic, I, Chan, DA, Sutphin, PD, Ray, P, Gambhir, SS, Giaccia, AJ, and Graves, EE. Oxygen sensitivity of reporter genes: implications for preclinical imaging of tumor hypoxia, Mol Imaging. 6: 219-28, 2007.
Glassford, AJ, Yue, P, Sheikh, AY, Chun, HJ, Zarashar, SY, Chan, DA, Reaven, GM, Quertermous, T, and Tsao, PS. HIF-1-mediated regulation of hypoxia- and insulin-induced expression of apelin in adipocytes, Am J Physiol Endocrinol Metab. 293: E1590-6, 2007.
Chang, EI, Loh, SA, Ceradini, DJ, Chang, EI, Lin, SL, Bastidas, N, Aarabi, S, Chan, DA, Freedman, ML, Giaccia, AJ, and Gurtner, GC. Age decreases endothelial progenitor cell recruitment through decreases in HIF-1a stabilization during ischemia, Circulation. 116: 2818-29, 2007.