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Understanding the impact of hypoxia dynamics on therapeutic response in breast cancer


Department of Oncology

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Prof E Hammond , Prof H Byrne , Dr Sarah Bohndiek No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

THE PROJECT:

THIS PROJECT HAS BEEN AWARDED FUNDING FROM CANCER RESEARCH UK (EUROPEAN/UK STUDENT ONLY).

Regions of hypoxia (low oxygen) occur in most if not all solid tumours. The presence of tumour hypoxia is significant as hypoxia drives many of the hallmarks of cancer and therapy resistance. Tumour hypoxia has been shown to correlate with poor patient outcome, regardless of the therapy modality used. Hypoxia results from an imbalance between oxygen delivery and consumption, however, what is often overlooked is that hypoxia is a fundamentally dynamic process i.e. the levels of oxygen change rapidly; exposure to fluctuating oxygen gradients has recently been proposed to further facilitate both metastatic spread and resistance to therapy. Research into the biological response to hypoxia is therefore essential to improve therapy and patient prognosis.

The Hammond lab have previously studied the DNA damage and replication stress response induced by constant levels of hypoxia (Olcina et al., Mol Cell 2103, Foskolou et al., Mol Cell 2017). This studentship will focus on how the biological response to dynamic hypoxia differs to that induced by constant levels. Preliminary data, which will form the basis of this project, suggests a marked difference in gene expression (genes induced in dynamic but not constant hypoxia), a significant difference in cell cycle progression/DNA replication and the induction of DNA damage by dynamic hypoxia but not constant. Using this approach may lead to the identification of potential synthetic lethal interactions in dynamic hypoxia i.e. mechanisms to kill cancer cells in this state.

This project forms part of a Cancer Research UK-funded multidisciplinary team including; Sarah Bohndiek (Cambridge), who will use high resolution photoacoustic imaging to map tumour blood oxygenation and Helen Bryne (Oxford) who will use the maps generated in the Bohndiek lab to generate in silico models of vascular architecture and function. This collaboration will ensure that the work done in the Hammond lab is physiologically relevant i.e. we are using conditions of dynamic hypoxia which actually occur in tumours. This project will include the use of cell and molecular biology techniques as well as gene expression studies (RNAseq, ChIP etc.).

This project has been awarded funding by Cancer Research UK.


THE TRAINING:
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.

PUBLICATIONS:
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.

Funding Notes

THIS PROJECT HAS BEEN AWARDED FUNDING FROM CANCER RESEARCH UK (EUROPEAN/UK STUDENT ONLY).

References

Whilst you must register three referees, the department may start the assessment of your application if two of the three references are submitted by the course deadline and your application is otherwise complete. Please note that you may still be required to ensure your third referee supplies a reference for consideration.

Academic references are strongly encouraged, though you may use up to one professional reference provided that it is relevant to the course.
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