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 radiotherapy rather than having their bladder surgically removed. Adding chemotherapy to radiotherapy makes the tumour more sensitive to radiation and improves outcomes at the expense of toxicity to surrounding normal tissues. We are trying to find effective drugs which have minimal effects, and the histone deacetylase inhibitor panobinostat is showing promise in this regard. We are elucidating the mechanisms underlying its radiosensitising properties, which should allow the development of more specific agents, thus reducing overall drug toxicity. Panobinostat downregulates the MRE11-RAD50-NBS1 complex post-transcriptionally, and we are using mass spectrometry (collaboration with Prof Benedikt Kessler) to study acetylation sites and dynamics in non-histone HDAC inhibitor protein targets involved in DNA repair pathways, which may be exploitable therapeutically (Figure 1). As chromatin regulation appears to be a major drive mechanism/hallmark of bladder cancer, we are also investigating bromodomain inhibitors as radiosensitisers. In another approach, we are looking to target agents directly to the bladder, through microbubble formulations (in collaboration with Profs Eleanor Stride and Bros Vojnovic) where drug can be released locally by focused ultrasound (Figure 2).
We are also looking for markers in patients' tumours to help patients choose between radiotherapy and surgery in MIBC. One such marker is the DNA damage signalling protein MRE11, which we found predicted patient survival after radiotherapy but not surgery, and this result was validated independently. Muscle-invasive bladder tumours have a truncated version of MRE11 which we hypothesise is acting in a dominant-negative manner and work is underway to investigate this. We are now seeking to exploit the TCGA and other data in MIBC to develop a gene signature and immunohistochemistry panel of biomarkers predictive of radiotherapy outcome. We have been involved in an exciting Citizen Science project, Reverse the Odds, where members of the public score our tumour samples, based on pattern recognition.
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.
Anne is Chief Examiner for the MSc in Radiation Biology in the Department of Oncology.
Groselj B, Scott H, Ruan J-L, Gorrill J, Kelly J, Anbalagan S, Thompson JM, Stratford MR, Jevons SJ, Hammond EM, Scudamore CL, Kerr M, Kiltie AE (2017) Radiosensitisation in vivo by histone deacetylase inhibition with no increase in early normal tissue radiation toxicity. Mol Cancer Ther doi: 10.1158/1535-7163.MCT-17-0011.
Walker AK, Kartsonaki C, Collantes E, Nicholson J, Gilbert DC, Kiltie AE (2017) MRE11 does not add predictive value to p16 and tumour infiltrating lymphocyte scores in anal cancer treated with chemoradiation. Br J Cancer 117:322-325.
Nicholson J*, Jevons S*, Groselj B, Ellermann S, Konietzy R, Kessler B, Kerr M, Kiltie [*equal contribution] (2017) E3 ligase cIAP2 mediates downregulation of MRE11 and radiosensitization in response to HDAC inhibition in bladder cancer. Cancer Res 77:3027-39.
Choi W, Ochoa A, McConkey DJ, Aine M, Hoglund M, Kim W, Real FX, Kiltie AE, Milsom I, Dyrskjot L, Lerner SP (2017) Genetic alterations in the molecular subtypes of bladder cancer: Illustration in the Cancer Genome Atlas dataset. Eur Urol doi: 72:354-365.
Kiltie AE and Browning L (2017) The impact of histological variants of urothelial carcinoma on clinical outcomes following trimodality bladder sparing chemoradiation. Eur Urol 72:61-63.
Lawson J, Robinson-Vyas RJ, McQuillan JP, Paterson A, Christie M, Kidza-Griffiths M, McDuffus L-A, Moutasim KA, Shaw EC, Kiltie AE, Howat WJ, Hanby AM, Thomas GJ, Smittenaar P (2017) Crowdsourcing for translational research: analysis of biomarker expression using cancer microarrays. Br J Cancer 116:237-45.
Jevons SJ, Green A, Lunter G, Kartsonaki C, Buck D, Piazza P, Kiltie AE (2015) High-throughput DNA sequencing identifies novel CtIP (RBBP8) variants in muscle-invasive bladder cancer patients. Bladder Cancer 1:31-44.
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 20:5435-45.
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.
Google scholar: https://scholar.google.co.uk/citations?user=ylKAilQAAAAJ&hl=en
Kristina Aare, MSc(Res) Student
Mark Dawidek, MSc student
Jong-Wei Hsu, Postdoctoral Researcher
Juri Na, Postdoctoral Researcher
Judith Nicholson, Postdoctoral Researcher
Edward Ottley, Postdoctoral Researcher
Jia-Ling Ruan, Postdoctoral Researcher
Alexa Walker, DPhil Student