title: Identification and characterisation of novel therapeutic combinations for head and neck cancer
Creators: name: Huang, Yuyao
Publisher: name: University of Liverpool Repository
Year: 2028

description: Squamous cell carcinoma of the head and neck (SCCHN) ranks as the sixth most prevalent cancer globally. Existing therapeutic strategies to treat this disease involve a combination of surgery, radiation, and/or chemotherapy. However, fewer than two-thirds of SCCHN patients survive beyond ten years, highlighting the ineffectiveness of current treatments, which are also compounded by severe side effects. Thus, there is unmet clinical need to develop more specific and efficacious therapies. As one of the original hallmarks of cancer, resistance to programmed cell death presents a significant therapeutic challenge. Until recently, there were limited FDA-approved therapeutic strategies specifically designed to overcome this resistance in patients with SCCHN. This thesis introduces two innovative approaches aimed at enhancing programmed cell death pathways in SCCHN, thereby addressing this critical clinical challenge.

Investigation of the TCGA database identified a significant correlation between BRD4 expression, a prominent BET protein, and the prognosis of patients with SCCHN. This observation prompts the exploration in Chapters 3 and 4 on whether pharmacological inhibition of BRD4 via BET inhibitor (BETi) could induce apoptosis, offering a potential therapeutic intervention for SCCHN. The tissue microarray (TMA) analyses shown abundant BRD4 expression in both tumour and adjacent epithelial nuclei, hinting a lack of tumour-specific cytotoxicity by BETi. To enhance apoptosis induction and reduce BETi dosage in tumour tissues, chapter 4 introduced BH3 mimetics, a pivotal apoptosis regulator, in combination with BETi. This combination increased apoptosis in SCCHN cell subsets, proposing the Birabresib and S63845 combination as an innovative therapeutic strategy for head and neck cancer, with synergy also observed in cell lines derived from other solid malignancies. The following mechanistic study indicated that Birabresib treatment increases BH3-only protein expression, rendering SCCHN cells more susceptible to BAX- and BAK-mediated apoptosis. Notably, despite the significant elevation of BIM, a key BH3-only protein, was observed following Birabresib treatment, it was not deemed central to the amplification process. This suggests the existence of a more complex mechanism, potentially involving unknown proteins activated by BETi, which in turn activate BH3-only proteins to trigger apoptosis. 

Chapter 5 shifts to an investigation into another therapeutic intervention targeting ferroptosis, a form of programmed cell death largely unexplored in SCCHN. This study first establishes that GPX4 is responsible for resisting ferroptosis in SCCHN cells, the cytotoxic effects of RSL3 can be amplified via inhibition of mTORC2, rather than by BRD4 inhibition. Further analysis reveals that the mTORC2-SREBP1-FASN signaling pathway contributes to this resistance. Given the absence of an mTORC2-selective but FASN-selective inhibitor GSK-2194169 in clinical trials, this research proposes a novel therapeutic strategy combining RSL3 with GSK-2194169 against head and neck cancer.

Overall, the findings reported in this thesis suggest two innovative therapeutic combinations to amplify programmed cell death in head and neck cancer for clinical: Birabresib and S63845 to simultaneously inhibit BRD4 and MCL-1 to enhance apoptosis, while RSL3 and GSK-2194169 to respectively inhibit GPX4 and FASN in order to potentiate induction of ferroptosis.