UTD Theses and Dissertations
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Browsing UTD Theses and Dissertations by Author "0000-0001-5103-337X (Castañeda, M)"
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Item Isolation of a FOXC2 Targeting Ligand for the Development of Cancer Metastasis Therapeutics(2019-05) Castañeda, Maria; 0000-0001-5103-337X (Castañeda, M); Lee, JiyongOften cancer patients face obstacles such as metastatic progression, recurrence and chemoresistance. These obstacles are correlated to poor patient survival rates, and high recurrence rates. At the forefront of these obstacles it the epithelial-mesenchymal transition (EMT). The epithelial-mesenchymal transition is responsible for the transformation of epithelial cells to mesenchymal cells. These mesenchymal cells have gained invasive and chemoresistant capabilities. In addition, EMT endows mesenchymal cells with higher CSC properties of selfrenewal, chemoresistance, immune evasion and higher proliferative rates. Once cancer cells have undergone EMT they are then able to travel to a secondary site within the body and initiate a secondary tumor. Thus, at the forefront of cancer metastasis is EMT progression. A central mediator of EMT is the transcription factor FOXC2. This transcription factor has been shown to be necessary and required for mesenchymal transformation of cells and acquisition of cancer stem cell (CSC) properties. Inhibition of FOXC2 has been shown to reverse EMT and reverse chemoresistance in a variety of cancer types. Here we describe the discovery of the first direct small molecule inhibitor of the transcription factor FOXC, MC-1-F2. This ligand has shown to bind to FOXC and have an affinity in the µM range with the ability to inhibit EMT and CSC properties. In addition, MC-1-F2 has shown in vitro to inhibit metastatic capabilities, increase chemosensitivity and restore AR expression. Mechanistic studies of the mode of action of MC-1-F2 have revealed that MC-1-F2 is able to inhibit FOXC2 phosphorylation through disruption of GSK3β and induce both apoptosis and autophagy. Further studies are still required to better understand the mechanism of action of MC-1-F2. Overall, MC-1-F2 the first direct small molecule inhibitor of FOXC2, will lead the way in the development of new cancer chemotherapeutic drugs for the treatment of metastatic cancer.