Determining effective radiation / drug combinations for paediatric cancers

Abstract

The five-year overall survival of paediatric cancer is currently ~80%; a significant improvement from a fiveyear overall survival of 58% - 68% in the 1970s. Thus, there is now a growing cohort of childhood cancer survivors who experience long-term health conditions due to dose intensification, and the pan-cytotoxicity of current treatments. Therefore, there is an urgent need for more effective, less toxic treatments for paediatric cancers.

 To identify new therapies, a bioinformatic all-pairs algorithm was adapted for use in a multiplex screen for interacting compounds (MuSIC). This approach facilitates the application of an FDA approved drug library in a combinatorial compound screen. MuSIC was applied to three areas of childhood cancer research: paediatric acute myeloid leukaemia (pAML), central nervous system (CNS)-pAML, and medulloblastoma; which represent a cohort of patients with well-reported long-term toxicities, and poor prognosis at relapse.  MuSIC identified a triple combination (TC) of alitretinoin, chenodiol and droperidol that induced caspase dependant apoptotic cell death in pAML cell lines. TC was most effective in 11q23 translocated cells with low basal PU.1 expression, significantly increased PU.1 expression with treatment, and decreased non-canonical NFκB expression. MuSIC also identified two antifungals, clotrimazole and econazole nitrate, which induced differential cell death between cells cultured in delipidated (DL) media to mimic the leukaemic-CNS environment, and normal pAML cell lines. Finally, the screen identified two triple combinations including both estropipate and posaconazole with either methenamine hippurate or pravastatin, which were effective up to 72 h with 2 Gy irradiation, in a SHH-subtype medulloblastoma cell line.

  This study identified agents with attractive safety profiles as single agents, and results to date demonstrate their effectiveness in vitro in pAML, CNS-pAML and medulloblastoma. Further validation is required in more clinically relevant models to elucidate their potential to be utilised clinically; to mitigate the acute and late side-effects caused by current standard of care treatments.  

Thesis is embargoed until 31 July 2027.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Leukaemia & Lymphoma NI
Supervisor	Kevin Prise (Supervisor) & Ken Mills (Supervisor)