Corson Lab Research
The Corson laboratory is interested in applying chemical biology approaches to problems in vision science. We use a variety of techniques from the chemical biology “toolbox,” including high-throughput compound screening, phage display, and biochemical approaches to compound mechanism of action, as well as more traditional techniques like tissue culture, expression analyses, protein purification, and molecular biology.
We are developing small molecules as probes and therapeutic leads for the common afflictions of age-related macular degeneration and retinopathy of prematurity, both of which are associated with abnormal excess blood vessel growth (neovascularization). We are also investigating the basic biology of, and potential therapeutic approaches for, the pediatric ocular tumor retinoblastoma, which is responsible for 1% of childhood cancer deaths and 5% of childhood blindness. Finally, we are also seeking novel targeted therapeutic approaches for the most common intraocular malignancy in adults, uveal melanoma. Further details of some of our projects are below.
Novel antiangiogenic compounds
There is a pressing need for novel small molecule drugs to block pathological neovascularization in the eye. In collaboration with Prof. Seung-Yong Seo (Gachon University) and Prof. Dulcie Mulholland (University of Surrey), we are producing novel antiangiogenic compounds based on natural products. For instance, we previously synthesized cremastranone, an antiangiogenic natural product, and developed a novel isomer of this compound with antiangiogenic activity against retinal endothelial cells. More recently, we have undertaken a structure-activity relationship study of this class of compounds and developed a new analog, SH-11037, with promising antiangiogenic activity in vitro and in vivo. We are testing this and other compounds in various angiogenesis models in collaboration with departmental colleagues Drs. Michael Boulton and Maria Grant. However, we are not only interested in developing potent new compounds, but also finding out how they work at the molecular level; our novel homoisoflavanone acts through the NF-κB pathway, and we are also pursuing other targets using biochemical techniques previously developed by Dr. Corson while working at Yale University. With targets in hand, we will be better able to understand not only how these molecules work, but how else we might target the same systems pharmacologically.
KIF14 as a novel oncogene
At the Ontario Cancer Institute/University of Toronto, Dr. Corson previously identified the mitotic kinesin KIF14 as a highly overexpressed gene in a minimal common region of somatic genomic gain in retinoblastoma. In this cancer, KIF14 is increased at the DNA, mRNA and protein levels. Importantly, we showed that overexpression of KIF14 is not only seen in retinoblastoma: we also saw overexpression in breast and lung tumors, and in both these cancers, increased expression was prognostic for poor outcome. KIF14 is crucial for efficient cytokinesis, although its exact functions remain enigmatic. We showed that siRNA-mediated knockdown of KIF14 greatly reduced the proliferation and tumorigenicity of cancer cells in vitro, suggesting its importance for the neoplastic phenotype. Others have since confirmed this in multiple cancer types, and recently, we helped identify transcription factors and microRNAs that might help drive KIF14 overexpression in ovarian cancer, in collaboration with Drs. Brenda Gallie and Brigitte Thériault (University of Toronto). However, questions remain: how does high KIF14 promote growth? Can we disrupt KIF14 function as a novel targeted therapeutic approach? The Corson lab is seeking to address these questions and develop the tools to do so, including developing novel models of retinoblastoma and methods for analyzing them.