An investigation of chromosomal instability survival mechanisms in cancer

Chromosomal instability (CIN) describes ongoing numerical and structural chromosomal aberrations in cancer cells, leading to intra-tumour heterogeneity and is frequently associated with polyploidy and aneuploidy. CIN is a frequent event in solid tumours and previous evidence has implicated CIN with acquired multidrug resistance, intrinsic taxane resistance and poor patient prognosis. In this thesis, I have attempted to explore mechanisms required for the initiation of CIN and the tolerance of this pattern of genome instability. Firstly, I have attempted to identify clinically relevant therapeutics that may have specific activity in CIN+ tumour cell lines. Focusing on a panel of colorectal cancer cell lines, classified as either CIN+ or CIN-, and treating them individually with kinase inhibitor and cytotoxic agent libraries, I demonstrated that CIN+ cell lines displayed significant intrinsic multidrug resistance. Next, I addressed if specific means to target CIN+ cells could be identified through pharmacological and RNA interference (RNAi) screens. No compounds were observed to be preferentially cytotoxic towards CIN+ cells in the pharmacological screen. A whole genome RNAi screen was performed to identify CIN+ specific survival pathways using isogenic cell line models of CIN. No genes were identified that conferred preferential cell death when silenced in CIN+ cells, despite sufficient statistical power to detect such targets. Using integrative genomics techniques and cell cycle data from this RNAi screen, I endeavoured to identify clinically relevant initiators of aneuploidy in colorectal cancer, that revealed both known and potential novel regulators of polyploidy. Finally, I endeavoured to identify a mechanistic basis for the taxane-sensitising phenotype associated with the silencing of the ceramide transporter, CERT, which may reveal means to target CIN+ cells. I demonstrated that CERT silencing sensitises paclitaxel-treated cells to cell death in a LAMP2-dependent manner that is associated with autophagy flux and may target death of multinucleated cells specifically

A population-scale temporal case–control evaluation of COVID-19 disease phenotype and related outcome rates in patients with cancer in England (UKCCP)

Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission