Calvin Kuo

Research in my laboratory is focused on basic and applied research on angiogenesis, as described below.

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 lab is comprised of 6 postdoctoral fellows, 3 graduate students and 2 undergraduates. 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. We have constructed over 70 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 achieve conditional knockout of these systems in adult mice to probe their functions in adult physiologic and tumor angiogenesis.

We are also probing the biology of vascular G-protein coupled receptors (GPCRs) through knockout and morpholino strategies in mice and zebrafish. GPCRs represent an emerging class of receptors regulating vascular biology, complementing the more intensively studied receptor tyrosine kinases. We have knocked out a novel vascular GPCR in mice, which results in an interesting phenotype of CNS hemorrhage with embryonic/perinatal lethality. We are studying the developmental phenotypes of these homozygous knockout embryos and are defining the expression patterns, ligands and signaling pathways of this receptor. We are also examining a second vascular GPCR in zebrafish whose knockdown results in profound deficits in vasculogenesis and angiogenesis. We are proceding with mouse knockouts as well as testing the ability of small molecule antagonists of this receptor to inhibit tumor growth in mice.

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.