Over 90% hereditary and sporadic colorectal cancers are caused by initial mutation in the adenomatous polyposis coli (APC) gene. The subsequent tumorigenesis is fueled by increased chromosomal instability, which rapidly incorporates oncogenic mutations. Hypermutated colorectal cancers are often lethal;therefore preventing early-stage cells from becoming malignant is key to combating this disease. The spindle and chromosomal segregation defects elicited by APC mutations would, in theory, trigger the mitotic checkpoint, cell cycle arrest, and apoptotic cell death, yet a great portion of mutant cells escape the checkpoint, becoming aneuploid and polyploidy-hallmarks of colon cancers. How do the earliest precancerous cells adapt for survival? Published work in the applicant's lab has revealed that Cdc42, a small GTPase of the Rho subfamily, is critical for intestinal stem cell survival, division, and differentiation. Strong preliminary data further demonstrate that Cdc42 is activated in early APCMin/+ mouse intestinal epithelia, prior to the onset of polyposis, and dramatically activated in intestinal microadenomas in mice carrying ?-catenin-dominant active mutation. Elevated Cdc42 appears to render tumor cells capable of survival and constructing aberrant crypt-like Wnt-secreting tumor microenvironments in vivo. The objective is to tackle the mechanism of pro-survival adaptation during early colorectal tumorigenesis, and to explore Cdc42-inhibition as a means of eradicating early-stage colorectal cancers. The hypothesis is that Cdc42 critically mediates pro-survival adaptation and niche construction in APC and/or ?-catenin mutant colorectal cancer cells;and targeting Cdc42 will effectively abrogate these prevalent types of colorectal cancer in vivo.
Aim I will explore the suppressive efficacy of Cdc42 inhibition on human colorectal cancer tumorigenesis;
and Aim II will explore the efficacy of Cdc42 inhibition on the tumorigenesis of a dietary carcinogen-induced colorectal cancer mouse model. This exploratory project composed of high-risk in vivo experiments is significant because it tests the efficacy of novel Cdc42 small molecule inhibitor on the natural pathogenesis of colon cancers, which will open the door for drug discovery and improvement. This project is, in our view, innovative because it explores the concept of inducing "synthetic lethality" by a new small GTPase inhibitor in a novel mouse colon cancer model that recapitulates the natural pathogenesis of human disease counterpart. Successful completion of this project is expected to greatly elevate our basic and clinical understanding of the mechanism of adaptation in colorectal cancer cells.
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