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Targeting cFLIP to inhibit residual cancer stem cells after chemotherapy

Robinson, Timothy 2017. Targeting cFLIP to inhibit residual cancer stem cells after chemotherapy. PhD Thesis, Cardiff University.
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The emergence of the cancer stem cell (CSC) hypothesis has helped to explain previously poorly understood clinical concepts such as metastases, late tumour recurrence and resistance to chemotherapy. Triple Negative Breast Cancer (TNBC) has the worst prognosis of all types of breast cancer with a more frequent relapse rate and reduced length of survival in metastatic disease. It has been shown to contain a higher proportion of CSCs than other types of breast cancer. Paclitaxel, a taxane in widespread use in breast cancer, induces apoptosis in a ligand-independent manner through the extrinsic apoptosis pathway. cFLIP is both an antagonist of this apoptosis pathway and can interfere with the ubiquitynation and subsequent degradation of both HIF1α and β-catenin, two molecules involved in CSC-signalling. Using a novel compound targeted against cFLIP, we wanted to assess whether its combination with paclitaxel effectively targeted CSCs. Using a combination of in vitro models of cancer stem/progenitor-like activity and the surrogate marker of CSCs, ALDH, we demonstrated that a number of chemotherapeutic agents, including paclitaxel, docetaxel and FEC increased CSC-like behaviour. A mathematical model demonstrated that paclitaxel increased the absolute number of CSCs after treatment suggesting that CSC-like activity was being induced. OH14, a novel inhibitor of c-FLIP developed in our laboratory, abrogated the paclitaxel-mediated induction of CSC-like activity in TNBC cell lines. While apoptosis may play a role in CSC viability in vitro, it did not appear to play a major role in OH14-mediated suppression of CSC acquisition following paclitaxel treatment. Instead, OH14 appeared to suppress CSCs through disruption of HIF1- α, as HIF1α-mediated signalling was increased by paclitaxel and abrogated by the addition of OH14. These beneficial effects of combinatorial OH14 were confirmed in vivo, where OH14 suppressed tumour initiation of TNBC xenografts and prevented relapse of paclitaxel treated tumours in a xenograft model of systemic treatment. cFLIP thus has a dual effect in both increasing apoptosis and targeting signalling in TNBC CSCs. In a breast cancer subtype in desperate need of novel therapeutic strategies, targeting cFLIP warrants further investigation and progression towards clinical trials.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Funders: Cancer Research UK
Date of First Compliant Deposit: 12 December 2017
Date of Acceptance: 12 December 2017
Last Modified: 13 Dec 2017 10:10

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