We are investigating DNA damage signalling and repair factors in bladder cancer to develop new radiotherapy-based treatments and to identify markers to select the most suitable treatments for individual patients.
Patients with muscle-invasive bladder cancer (MIBC) can be treated by surgical removal of their bladder or radiotherapy-based treatments. Radiotherapy has the advantage of bladder preservation. Adding chemotherapy to radiotherapy makes the tumour more sensitive to radiation and improves outcomes but adds to the side effects of treatment. We have found that muscle-invasive tumours repair their DNA less efficiently than normal tissues and we are trying to exploit this difference by using radiosensitising drugs which target the remaining DNA repair pathways, thus damaging the tumour more than the surrounding normal tissues. Such drugs include gemcitabine, which is already in clinical use as a radiosensitiser and the histone deacetylase inhibitors. Further understanding of the mechanisms of action of these drugs will allow the development of more specific agents, which should result in reduced side effects.
We are also looking for markers in patients’ tumours which could help us predict which patients would benefit most from a particular treatment, and this could help patients make their choice between surgery and radiotherapy-based treatments. One such marker is the DNA damage signalling protein MRE11, which we found predicted patient survival after radiotherapy but not surgery, in two groups of patients. We are testing this marker further in tissue from patients treated in two large randomised clinical trials. Muscle-invasive bladder tumours seem to have a shortened version of MRE11 and this could be important in terms of our clinical findings, so we are studying this in more detail. We have also found that a genetic variant of the MRE11 gene found in patients’ blood also predicted for radiotherapy outcomes and we are investigating the underlying mechanisms further. We are also exploring other predictive markers in tissue microarray samples from our patients, in an exciting Citizen Science project, where members of the public score our tumour samples, based on pattern recognition.
Fig 1. Bladder cancer cells stained for two molecular markers following irradiation.
Fig 2. Consistency of IHC staining for MRE11 across three clinical trial sites.
Anne Kiltie is Professor of Experimental Clinical Oncology and a CRUK Senior Clinical Group Leader at the CRUK/MRC Oxford Institute for Radiation Oncology. She is also an Honorary Consultant Clinical Oncologist at Oxford University Hospitals NHS Trust. Between 2001 and 2009 she was a Senior Lecturer/Honorary Consultant Clinical Oncologist at Leeds Institute of Molecular Medicine and St James' University Hospital, Leeds. She was previously a Clinical Research Fellow at the Imperial Cancer Research Fund (ICRF) Clare Hall Laboratories in Hertfordshire. Her clinical training was undertaken at the Christie Hospital, Manchester, and Cookridge Hospital, Leeds. She studied Medicine at Sidney Sussex College, Cambridge, and Clinical Medicine at Balliol College, Oxford.
Kerr M, Scott H, Groselj B, Stratford M, Karaszi K, Sharma N, Kiltie AE (2014) dCK expression may underpin gemcitabine sensitivity in bladder cancer. Clinical Cancer Research doi:10.1158/1078-0432.CCR-14-0542.
Cazier JB, Rao RS, McLean CM, Walker AK, Wright BJ, Jaeger EEM, Katsonaki C, Marsden L, Yau C, Camps C, Kaizaki P, The Oxford-Illumina WGS500 Consortium, Taylor J, Catto JW, Tomlinson IPM*, Kiltie AE*, Hamdy FC*[*equal contribution] (2014) Whole genome sequencing of bladder tumours reveals somatic mutations in CDKN1A and clinicopathological associations with mutation burden. Nat Commun 5:3756.
Teo MTW, Dyrskjøt L, Sjöström S, Nsengimana J, Buchwald C, Snowden S, Morgan J, Bjerggaard Jensen J, Johansen C, Harland M, Elliott F, Hurst C, Knowles MA, Taylor G, Barrett JH, Borre M, Ørntoft TF, Bishop DT, Kiltie AE (2014) Germline MRE11 variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer. Ann Oncol 25:877-883.
Kristina Aare, DPhil Student
Jessica Gorrill, FHS Student
Maria Heinz, MSc student
Martin Kerr, Postdoctoral Researcher
Eva McGrowder, Postdoctoral Researcher
Judith Nicholson, Postdoctoral Researcher
Jia-Ling Ruan, Postdoctoral Researcher
Alexa Walker, DPhil Student