The Laboratory of Calvin Kuo, MD, PhD
Front Row (L to R): Ye Yuan, Frank Kuhnert, PhD, Amy Zhou, Jenny Yuan, MD, Brian Lu, MD, PhD,
Ting Wang, Quoc Tri Ho
Back Row (L to R): Mike Mancuso, Calvin Kuo, MD, PhD, Matt Goldstein, Nina Yang, Mark Lee,
MD, PhD, Kevin Wei, Akifumi Ootani, MD, PhD
Research in the Kuo laboratory is focused on the biologic characterization of novel molecules regulating angiogenesis, and assessment of their use for anti-angiogenic therapy of cancer. The use of anti-angiogenic therapy for malignancies has recently found validation in phase III trials of anti-VEGF antibodies for colon cancer. We have used adenoviruses to enable high-level expression of circulating ectodomains of receptors implicated in tumor angiogenesis, such as the VEGF, Tie2 and PDGF receptors. Single i.v. injections of these adenoviruses produces durable ectodomain expression in mice for ~ 3 weeks, during which the respective ligands are neutralized by the circulating ectodomain, and severe inhibition of tumor growth is observed. We have constructed over 30 adenoviruses encoding putative anti-angiogenic proteins and are assessing their ability to provide anti-angiogenic and anti-tumor activity singly and in combination. The identification of novel anti-angiogenic molecules will hopefully enable the development of cocktails of anti-angiogenic therapeutics having superior efficacy to VEGF blockade. In related activities, we are exploring the molecular basis of tumor resistance to VEGF blockade, and are using adenoviruses expressing ectodomains of the VEGF, Tie2 and PDGF receptors to acheive conditional knockout of these systems in adult mice to probe their functions in adult physiologic and tumor angiogenesis.
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We are also probing the biology of novel angiogenic mediators using conventional and conditional knockouts in mice via homologous recombination. G-protein coupled receptors (GPCRs) represent an emerging class of receptors regulating vascular biology, complementing the more intensively studied receptor tyrosine kinases. We are inactivating several novel vascular GPCRs in mice, and are studying the developmental phenotypes of these homozygous embryos. Additionally, we are defining the expression patterns, ligands and signaling pathways of these receptors.
A third activity in the lab revolves around an unexpected finding that adenoviral expression of a soluble Wnt inhibitor, Dickkopf-1, produces abrupt cessation of proliferation in the epithelium of both the adult small and large intestine. These results implicate endogenous Wnt proteins as essential growth factors for the adult intestinal epithelium. Current efforts in this area are exploring the roles of Wnt proteins in the stimulation of intestinal epithelial proliferation and as novel therapies for mucosal repair in inflammatory bowel diseases. Adenoviral expression of Dickkopf-1 also represents a conditional knockout of Wnt function in adult animals, enabling identification of additional Wnt functions in adult physiology.
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Jenny Yuan, MD, Kuo Lab Manager |
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Selected publications
- Kuo CJ, Farnebo F. A., Yu, E. Y., Christofferson R., Swearingen, R. A., Carter, R., Von Recum, H. A., Yuan, J., Kamihara J., Flynn, E., D'Amato R., Folkman, J. and Mulligan, R. C. Comparative efficacy of adenovirus-encoded antiangiogenic gene products. Proc. Natl. Acad. Sci. USA 98 4605-4610 (2001).
- Kuo CJ, Farnebo FA, Becker C and Folkman J. VEGF-targeted antiangiogenic gene therapy. In: Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation, 2nd Ed. (EC Lattime, Ed.) Academic Press ( New York) (2002).
- Kuhnert F., Davis CR, Wang H, Chu P, Lee M., Yuan J., Nusse R and Kuo CJ. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci U S A. Jan 6; 101(1): 266-71. (2004).
- Jacobi J, Tam BY, Sundram U, Degenfeld Gv G, Blau HM, Kuo CJ, Cooke JP. Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis. Gene Ther. Feb; 11(3): 302-9. (2004).
- Hoffman J., Kuhnert F., Davis CR and Kuo CJ. Wnts as essential growth factors for the adult small intestine and colon. Cell Cycle, in press (2004).