Discovery of small molecule inhibitors targeting oncogenic CHD1L with preclinical activity in colorectal cancer

Includes bibliographical references. ; Spring ; The majority of colorectal cancers arise from dysregulation in the Wnt signaling pathway. Aberrant Wnt signaling is associated with tumor formation, metastasis, and drug resistance. Many current therapeutic strategies attempt to target downstream effectors of the Wnt pathway, most notably protein-protein interactions that mediate formation of b-catenin/TCF4 complexes. These strategies have had limited clinical success, due in part to there being a limited amount of known druggable targets involved with activating transcription of Wnt target genes. In an attempt to develop more effective therapies for colorectal cancer, this manuscript describes our efforts to validate CHD1L as a novel druggable target involved in Wnt signaling and identify the first known small molecule inhibitors of CHD1L. CHD1L is an oncogene involved in drug resistance, anti-apoptotic mechanisms, tumor progression, and metastasis in a variety of solid tumors. Prior to the work presented in this dissertation, little was known about the mechanistic role of CHD1L in colorectal cancer and no direct link had been established between CHD1L and Wnt signaling. To validate CHD1L as a potential drug target in the Wnt pathway, we examined gene expression data from colorectal cancer patients and performed in vitro experiments to determine if CHD1L was involved in Wnt signaling in colorectal cancer. Our results showed that CHD1L expression positively correlates with activated Wnt signaling, and that its expression alone is able to modulate Wnt target gene expression in colorectal cancer cell lines. Overexpression of CHD1L was also found to promote the malignant phenotype in colorectal cancer by upregulating mesenchymal gene expression and promoting cancer stem cell proliferation. Additionally, we found that CHD1L interacts directly with members of the TCF-transcriptional complex. These results indicate that CHD1L is a potential novel druggable target to modulate Wnt signaling. While gene expression and ...