Developing modulators of tumour hypoxia through inhibition of cellular oxygen consumption

Thesis

Tumor hypoxia, common in solid malignancies, is strongly associated with poor clinical outcomes due to its role in promoting tumor development and radiation therapy resistance. Previous attempts to overcome tumor hypoxia by increasing oxygen supply to hypoxic regions, including hyperbaric oxygen chambers, oxygen mimetics and vascular remodelling, have yielded limited clinical success. Mathematical modelling, in vitro and in vivo studies have demonstrated that reducing the oxygen consumption rate (OCR) of tumour cells is an effective strategy in increasing local oxygen availability to overcome diffusion-limited hypoxia. High throughput screening work by the Higgins group has identified fenofibrate, a hyperlipidemia prodrug, to strongly reduce OCR in vitro.5 Fenofibrate is an inhibitor of Complex I in the electron transport chain. However, in vivo fenofibrate is rapidly and completely metabolised to fenofibric acid, a compound which has no effect on OCR.

The present work assesses whether fenofibrate, a well-tolerated and widely used compound, can be chemically modified to evade metabolic degradation while maintaining OCR inhibition to become an effective therapeutic in modifying tumour hypoxia. Novel Complex I inhibitors and fenofibrate derivatives, 1 and 2, were synthesized through a collaboration with the Schofield group in the Department of Chemistry. Both 1 and 2 demonstrated an increased potency for OCR inhibition in vitro compared to their parent compound. In 3D spheroids, 1 and 2 effectively abolished hypoxia in the micromolar range. However, 1 and 2 were unable to reduce tumour hypoxia in vivo at oral dosing schedules determined by their toxicity and drug solubility limits. The high hydrophobicity and poor solubility of 1 and 2 limited the selection of in vivo drug vehicles to predominantly oils, which were deemed unsuitable for intraperitoneal and intravenous routes of administration.

A series of 26 new fenofibrate derivatives, termed series V, was synthesized by the Schofield group. Series V compounds were developed for improved solubility while maintaining efficacy in OCR inhibition. Series V compounds which outperformed fenofibrate in OCR inhibition in vitro were tested in spheroids, where several compounds showed promising efficacy in abolishing hypoxia. This work will guide the selection of a more suitable in vivo candidate molecule for tumour hypoxia modification.

Authors: Machado, N

• DOI: 10.5287/ora-be278v5bn
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: metabolism; mitochondria metabolism; radiotherapy; small molecule inhibitor; tumour hypoxia
• Subjects: Radiotherapy; Tumour Hypoxia; Cell metabolism; Oncology