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Title: Pre-clinical evaluation of a novel small molecule inhibitor of FLIP in colorectal cancer
Author: Fox, Jennifer Patricia
ISNI:       0000 0004 6425 312X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Northern Ireland. Not only this but CRC also has poor overall survival rates particularly in the advanced disease setting mainly due to drug resistance to standard-of-care chemotherapeutics. One of the mechanisms of drug resistance is the upregulation of the anti-apoptotic protein FLIP (Fas-associated death domain (FADD)-like interleukin-1 b-converting enzyme (FLICE) Inhibitory Protein) which has been shown to be overexpressed in various types of cancer. By binding to the adaptor protein FADD, FLIP elicits its anti-apoptotic effects by disrupting procaspase-8 (FLICE) homo-dimizeration at the Death Inducing Signalling Complexes (DISCs) formed by activated cell surface death receptors, promoting cell survival. Previous studies have shown correlation between FLIP overexpression and poor patient prognosis, providing suggestive desirability of FLIP as a therapeutic target in cancer therapy. Moreover, our laboratory has shown that downregulating FLIP using FLIP targetting siRNA or antisense oligonucleotides promotes apoptotic cell death. Due to these findings, small molecule inhibitors (SMIs) of FLIP have been developed to target FLIP specifically by disrupting FLIP-FADD interaction. This thesis focused on one FLIP SMI (FLIPi_1) to determine not only its mechanism of action but its ability to cause cell death as a monotherapy. Further work in this thesis also demonstrated FLIPi_1 ability to resensitise CRC cell lines to other desirable treatments such as rTRAIL and standard-of-care chemotherapeutics. These results demonstrate FLIPi_1 as a potential and promising therapeutic in CRC. Previous in vivo work showed FLIPi_1 to have a rapid turnover rate. Nanodelivery carriers have the potential to maximise drug delivery to target cells. This thesis shows the formulation of a polymeric nanoparticle delivery system for FLIPi_1 and its therapeutic effect both in vitro and in vivo. The results obtained demonstrated similar efficacy between free FLIPi_1 and encapsulated FLIPi_1 in 3 CRC cell lines tested.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available