Our research links basic science with clinical applications and focuses on understanding the mechanisms behind tumour resistance to radiation.
The main goal of our research is sensitising cells to radiation by blocking mechanisms that control cell survival. Specifically we are interested in oncogenically activated signal transduction pathways that exert a radioprotective effect on tumour cells. The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionising radiation without altering the sensitivity of normal tissues.
In the past, our research has shown that the EGFR-Ras-PI3K-PTEN-Akt pathway appears to be the major radioprotective pathway active in most solid tumours, and therefore this pathway presents targets that could be manipulated in a clinical setting to modify the radiation response. We have shown that a specialised DNA repair enzyme, DNA polymerase theta (POLQ), is overexpressed by tumour cells and that depletion of this enzyme makes cells more sensitive to radiation. Importantly, normal healthy cells do not appear to express POLQ and are therefore not affected by its inhibition. We also found that patients with high levels of POLQ expression have a worse prognosis. This would make POLQ an ideal therapeutic target for improving the effectiveness of radiotherapy without increasing normal tissue toxicity.
Figure 1. High POLQ expression correlates with a poor prognosis. Univariate analysis of relapse-free survival in 152 breast cancers patients with POLQ expression divided in high and low expression groups by median value. From Higgins et al., 2010a
We are also interested in improving radiotherapy by reducing tumour hypoxia (low levels of oxygen in the tissue). One of the main reasons for the resistance of tumours to radiotherapy is the presence of large hypoxic regions that are significantly more resistant to radiation. One way of alleviating tumour hypoxia is to reduce the oxygen consumption of the fast growing cells at the tumour periphery so that more oxygen becomes available to the hypoxic regions. A high-throughput screen conducted by our laboratory identified drugs that reduce oxygen consumption in tumour cells that could be used clinically to reduce tumour hypoxia.
Figure 2. A drug identified by our laboratory that reduces hypoxia. The graph on the left shows the reduction in oxygen consumption following treatment with the drug in tumour cells grown as a monolayer. The panel on the right shows the reduction in the hypoxic core of tumour cells grown in spheroids, which mimic solid tumours. After 24 hours of treatment with this drug, the hypoxia in the centre of the spheroid is completely abolished.
Gillies McKenna, Professor of Radiation Oncology and Biology, has been Director of the CRUK/MRC Oxford Institute for Radiation Oncology since 2005, and Head of the Department of Oncology at the University of Oxford since its formation in 2010. Prior to that, he was Chairman and Henry K. Pancoast Associate Professor of Radiation Oncology at the University of Pennsylvania School of Medicine, rising to Professor in 1995. He has received several awards and honours including the Weiss Medal from the Association for Radiation Research, the Frank Ellis Medal from the Royal College of Radiologists, the Roentgen Medal from the Deutches Roentgen Museum and the Gold Medal from the Royal College of Radiologists.
Higgins G, Harris A, Prevo R, Helleday T, McKenna WG, and Buffa F (2010). Overexpression Of POLQ Confers a Poor Prognosis In Early Breast Cancer Patients. Oncotarget, 1(3):175-84.
Higgins G, Prevo R, Lee Y, Helleday T, Muschel R, Taylor S, Yoshimura M, Hickson I, Bernhard E, and McKenna W (2010). A siRNA Screen of Genes Involved in DNA Repair Identifies Tumour Specific Radiosensitisation by POLQ Knockdown. Cancer Res, 70(7):2984-93.
Qayum N, Muschel R, Im JH, Balathasan L, Koch C, Patel S, McKenna WG, and Bernhard E (2009). Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res, 69(15):6347-54.
Thomas Ashton, Postdoctoral Researcher
James Coates, DPhil Student
Cynthia Eccles, DPhil Student
Giacomo Pirovano, DPhil Student
Remko Prevo, Laboratory Manager
Gagan Tiwana, DPhil Student