Understanding the impact of hypoxia dynamics on therapeutic response in breast cancer
Nominating supervisor: Ester Hammond
THIS PROJECT HAS RECEIVED FUNDING FROM CANCER RESEARCH UK (UK/EUROPEAN STUDENT ONLY)
Hypoxia, resulting from an imbalance between oxygen delivery and consumption, is a common feature of most solid tumours associated clinically with: cellular heterogeneity and genomic instability; chemo- and radio-resistance; and poor prognosis, particularly in cancers of hormone sensitive tissues such as the breast. Overlooked by many of these studies is the fact that hypoxia is a fundamentally dynamic process; exposure to fluctuating oxygen gradients has recently been proposed to further facilitate both metastatic spread and resistance to therapy.
This project forms part of a multidisciplinary team including; Sarah Bohndiek, who will use high resolution photoacoustic imaging to map tumour blood oxygenation and Helen Bryne who will use the maps generated in the Bohndiek lab to generate in silico models of vascular architecture and function. Together this will provide mechanistic insight into the causes of transient blood flow changes and make predictions of associated oxygen partial pressure (pO2) in tumour tissue to inform in vitro experiments.
This studentship will be based in the Hammond lab which has specialist hypoxia chambers that provide constant levels of hypoxia or dynamic hypoxia on the timescale of both hours and minutes. This will allow us to mimic the physiologically relevant conditions determined by our collaborators in order to ask important questions relevant to the treatment of breast cancer. For example, how the response to standard-of-care agents is impacted by dynamic hypoxia; how the DNA damage response, which the Hammond lab have described extensively in response to constant hypoxia, is altered in dynamic conditions and finally, the identification of potential synthetic lethal interactions in dynamic hypoxia.
Overall, this multi-disciplinary and collaborative project will provide us with fundamental insight into the biological response to dynamic versus constant hypoxia and the relative therapy resistance. Most importantly, it will also allow us to test the interaction of novel therapies with the hypoxic solid tumour microenvironment. This project has been awarded funding by Cancer Research UK.
The student will develop expertise in the field of hypoxia and particularly the in vitro systems/models available. A key part of this studentship will be the exposure to a multi-disciplinary team with the opportunity to collaborate with experts in both the mathematical and imaging labs. It is envisioned that the student will visit the Bohndiek lab in Cambridge to gain first-hand experience.
Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication. Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, D'Angiolella V, Myers WK, Domene C, Flashman E, Hammond EM. Mol Cell. 2017 Apr 20;66(2):206-220
Preclinical testing of an ATR inhibitor demonstrates improved response to standard therapies for esophageal cancer. Leszczynska KB, Dobrynin G, Leslie RE, Ient J, Boumelha AJ, Senra JM, Hawkins MA, Maughan T, Mukherjee S, Hammond EM. Radiother Oncol. 2016 Nov;121(2):232-238
Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. Leszczynska KB, Foskolou IP, Abraham AG, Anbalagan S, Tellier C, Haider S, Span PN, O'Neill EE, Buffa FM, Hammond EM. J Clin Invest. 2015 Jun;125(6):2385-98.