Identification of novel synergistic drug combinations with statins in paediatric AML

Abstract

Acute myeloid leukaemia (AML) is complex, heterogenous blood cancer that is treated with high-dose chemotherapeutics that are associated with severe short- and long-term side effects. With 5-year overall survival rates of 60-70%, new treatment approaches are essential to improve patient outcomes. The cholesterol biosynthesis pathway has been shown to be dysregulated in cancers such as AML. The expression of cholesterol pathway genes can affect patient outcomes and response to treatment. This thesis investigated the expression of cholesterol pathway genes in publicly available AML patient datasets to identify potential therapeutic targets, prognostic indicators and predictors of treatment response. There were several genes includingFDFT1, LDLR, HMGCS1, OSBPL5, STARD3 and VLDLR that were significantly overexpressed in AML patient samples compared to healthy controls. Genes such as VLDLR had relatively low expression in the healthy controls suggesting it as a promising therapeutic target. The upregulation of LDLR and SREBP2 was associated with reduced overall survival and poor prognosis (based on overall survival and evert-free survival) suggesting a potential use of these genes as prognostic indicators in AML.

Statins target the cholesterol biosynthesis pathway and have been previously identified as a hit in a single-agent drug repurposing screen in primary murine AML models. Combination therapies with repurposed drugs offer a cheaper, more effective option to standard chemotherapy. This thesis focused on identifying novel, synergistic drug combinations with statins in paediatric AML. High-throughput drug screening of FDA-approved drugs (n = 1971) was performed in THP-1 and MV4-11 cell lines and identified hits based on cell viability (<50%). Although the primary aim of this thesis was synergistic drug combinations, the single agent drug screens identified novel single agents in AML that could be investigated further. 146 drug hits appeared in both AML cell lines and were used in a combination screen with pitavastatin calcium. Following synergy calculations, several synergistic drug combinations with pitavastatin calcium were identified including: GSK2124658, Epothilone B and pemetrexed. These novel synergistic drug combinations were validated in THP-1 andMV4-11 cell lines. This thesis has shown that these combinations are effective in an in vitro setting but further work in vivo is required to investigate the clinical translatability of these combinations.

Thesis embargoed until 30 September 2026.

Date of Award	Sept 2024
Original language	English
Sponsors	Little Princess Trust
Supervisor	Catriona Kelly (Supervisor) & Kyle Matchett (Supervisor)