Investigation of the contribution of redox stress to the therapy resistance of cells experiencing cycling oxygen levels

THE PROJECT
Hypoxia is a major barrier to successful cancer treatment as the more hypoxic a tumour, the less well patients respond. This project will focus on the physiologically relevant condition of cyclic hypoxia in which cancer cells experience fluctuations in oxygen levels as opposed to constant exposure to hypoxia. Recent findings from the Hammond lab suggest that the cellular response to cyclic hypoxia differs significantly from constant exposure and that this includes the contribution of changes in REDOX in the cyclic conditions. Understanding the dynamics of REDOX elements in biological systems is of major importance because of its roles in basic biology, agriculture, disease and medicine. However, quantifying changes in REDOX elements remains a major challenge for chemical biology. Key elements involved in defining the cellular REDOX environment include reactive oxygen species (ROS), reactive nitrogen species (RNS), sulfur-containing molecules including H2S and glutathione (GSH), hypoxia (lower than normal [O2]), and post-translational modification of amino acid residues in proteins. The relative concentration and interaction of these components defines the cellular REDOX environment, which is intrinsically linked to metabolism through processes such as glycolysis and oxidative phosphorylation. Cellular metabolism and REDOX state are in turn linked to epigenetic regulation, because modifications to chromatin involve consumption of important metabolites and REDOX-active molecules. Consequently, both metabolism and the REDOX environment can affect transcription through chromatin remodelling, and therefore cell fate decisions are closely linked to changes in metabolic activity and the REDOX environment. This project will investigate REDOX stress in cyclic hypoxia and how this contributes to biological response and sensitivity to cancer therapies. Specific approaches will include, for example, gene expression analysis (RNA-seq) of cells in both constant and cyclic hypoxia. This project will also benefit from early access to probes being generated in the Conway lab which will allow characterisation of REDOX stress.

THE TRAINING
This project offers unique access to a multi-disciplinary network of scientists brought together by the recently funded EPSRC programme grant led by Profs Conway and Hammond. The student will join this team and attend all programme meetings and will therefore interact with biologists, chemist and imaging scientists in a number of departments and indeed Universities (Kings College London is part of the programme). The student will be jointly supervised by Conway and Hammond and meet regularly (every 3 weeks) with both supervisors along with other members of the team. We (Conway and Hammond) have been collaborating for 10 years and have successfully graduated 4 DPhil students who have all had unprecedented training in chemical biology. Of these 4 students, 2 moved onto post doc positions, 1 has joined a small biotech company and the 4th is training in patent law

PUBLICATIONS
Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs. O’Connor LJ, Cazares-Körner C, Saha J, Evans CN, Stratford MR, Hammond EM, Conway SJ. Nature Protocols. 2016 Apr;11(4):781-94.

CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. Cazares-Körner C, Pires IM, Swallow ID, Grayer SC, O’Connor LJ, Olcina MM, Christlieb M, Conway SJ, Hammond EM. ACS Chem Biol. 2013 Jul 19;8(7):1451-9.

Clinical Advances of Hypoxia-Activated Prodrugs in Combination with Radiation Therapy. Mistry IN, Thomas M, Calder EDD, Conway SJ, Hammond EM. Int J Radiat Oncol Biol Phys. 2017 Aug 1;98(5):1183-1196.