Anne Kiltie BM, BCh, MA, DM, MRCP(UK), FRCR
Dr Anne Kiltie
Aberrant DNA double strand repair mechanisms in bladder cancer .
The development of breaks in both strands of DNA (DNA double-strand breaks) is a normal part of cell division and differentiation. Accurate repair of these breaks is essential to maintain genome stability, preventing replication and propagation of DNA with genomic mistakes. Pathways that repair DNA double strand breaks have been identified and include homologous recombination (HR), non-homologous end joining (NHEJ) and a less well understood repair mechanism, microhomology-mediated end joining (MMEJ). MMEJ is a pathway particularly prone to errors and as a result can cause increased levels of chromosomal translocations and deletions, contributing to an increase in oncogenic chromosome rearrangements that are the hallmark of cancer cells. One of the key areas of research focus is to investigate the mechanisms underlying the defective NHEJ and the MMEJ mechanisms seen in muscle invasive bladder cancer, and to exploit this clinically in combined radiotherapy/biological treatments. Such exploitation could include targeting of HR, to increase the therapeutic ratio. They tyrosine kinase inhibitor imatinib and the histone deacetylase inhibitor panobinostat have shown promise in this regard.
DNA damage signalling proteins as biomarkers for radiotherapy and chemotherapy effectiveness in bladder cancer.
There are currently limited data comparing surgery and radiotherapy with or without concurrent chemotherapy for treatment of muscle invasive bladder cancer and selection of therapy is currently based on patient choice with recommendations from their urologist and oncologist. Identifying which patients are likely to benefit from radiotherapy would help to rationalise its use in the management of these patients. Earlier studies have demonstrated that patients who have a higher expression of the DNA damage signalling protein MRE11 have improved survival after radiotherapy compared with those with low expression levels, indicating that MRE11 is a biomarker for radiotherapy outcome in muscle invasive bladder cancer. Current research is focussed on developing and validating a clinically-useful assay for MRE11, in collaboration with the Paterson Institute in Manchester, Leeds Institute of Molecular Medicine and the University of Birmingham, and to establish the role of other such biomarkers. As part of the validation process, potential biomarkers are being tested using tissue samples from large UK bladder cancer radiotherapy randomised trials (BCON and BC2001) and successful biomarkers and assays will then be tested in randomised controlled clinical trials. This should ultimately allow patient selection for optimal bladder cancer treatment, thus increasing overall cure rates.
Muscle invasive bladder cancer is treated primarily with surgical removal of the bladder (cystectomy) or radical radiotherapy. Bladder-preserving treatments include radiotherapy given together with the chemotherapy cisplatin. However, many elderly or unfit patients may not be able to tolerate the toxicity of cisplatin and an alternative in these patients is the chemotherapy gemcitabine (given at a lower dose than normal) in combination with radiotherapy, so-called GemX. At this dose, gemcitabine is believed to enhance radiotherapy by increasing the radiosensitivity of cancer cells. Studies have shown that GemX achieves a high response rate in patients with muscle invasive bladder cancer with long-lasting local control and acceptable toxicity, sparing patients from removal of their bladder. Being able to identify and predict which patients are most likely to benefit from GemX treatment would allow patient selection to optimise cure rates, spare likely non-responders from toxicity and allow them to be directed to potentially more effective treatments.
Gemtrans (measurement of gemcitabine metabolites in blood and urine as predictors of response to GemX bladder radiotherapy, NCT01343121) is a prospective observational feasibility study that is testing the hypothesis that plasma, peripheral blood mononuclear cell and urine levels of gemcitabine and its metabolites predict response to GemX chemoradiation at first check cystoscopy (a medical procedure used to examine the bladder) which is done three months after radiotherapy. In the longer term Gemtrans will also evaluate any potential impact of MRE11 expression and expression of gemcitabine metabolizing enzymes on the study results and clinical outcome. Molecular analysis will also be undertaken to see whether there are any genetic variations that are associated with expression patterns or outcome.
Dr Anne Kiltie is a Clinical Group Leader at the Gray Institute for Radiation Oncology and Biology within the University of Oxford. She is also an Honorary Consultant Clinical Oncologist at Oxford University NHS Trust.
Dr Kiltie joined the University of oxford in October 2009 after eight years as a Senior Lecturer/Honorary Consultant Clinical Oncologist (Radiotherapist) at St James' University Hospital and Leeds Institute of Molecular Medicine, Leeds (Nov 2001-Sept 2009). prior to that she was a Clinical Research Fellow at the Imperial Cancer Research Fund (ICRF) Clare Hall Laboratories in Hertfordshire (Oct 1999 - Oct 2001).
Dr Kiltie is a member of several professional organisations including the Royal College of Radiologists, ESTRO, the British Association of Urological Surgeons and the British Uro-oncology Group. She had authored or co-authored 47 publications and been invited to present her work at national and international conferences.
Currently available DPhil projects:
- Effects of MRE11/RAD50/NBS1 isoforms on response to cancer therapy. Supervisors: Dr Anne Kiltie & Dr Anderson Ryan (REF: GI14AK1)
Groselj B, Kerr M, Kiltie AE (2013) Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression. Radiother Oncol in Press, doi 10.1016/j.radonc.2013.06.021
Qiao B, Kerr M, Groselj B, Teo MTW, Knowles MA, Bristow RG, Phillips RM, Kiltie AE (2013) Imatinib radiosensitises bladder cancer by targeting homologous recombination. Cancer Res 73:1611-20.
Teo MTW, Landi D, Taylor C, Elliott F, Vaslin L, Cox DG, Hall J, Landi S, Bishop DT, Kiltie AE (2012) The role of microRNA-binding site polymorphisms in DNA repair genes as risk factors for bladder cancer and breast cancer and their impact on radiotherapy outcomes. Carcinogenesis 33:581-6.
Choudhury A, Swindell R, Logue JP, Elliott PA, Livsey JE, Wise M, Symonds P, Wylie JP, Ramani V, Sangar V, Lyons J, Bottomley I, McCaul D, Clarke NW, Kiltie AE, Cowan RA (2011) Phase II study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer. J Clin Oncol 29:733-8.
Choudhury A, Nelson LD, Teo MT, Chilka S, Bhattarai S, Johnston C, Elliott F, Lowery J, Taylor CF, Churchman M, Bentley J, Knowles MA, Harnden P, Bristow RG, Bishop DT, Kiltie AE (2010) MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle invasive bladder cancer. Cancer Res 15:7017-7026.
B Groselj B, Sharma N, Hamdy FC, Kerr M, Kiltie AE (2013) Histone Deacetylase Inhibitors as Radiosensitisers – Effects on DNA Damage Signalling and Repair. BJC 108: 748-54.
Sharma NL, Groselj B, Hamdy FC, Kiltie AE (2013) The emerging role of HDAC inhibitors in urological cancers. BJUi 111:537-42.
Qiao B, Scott GB, Elliott F, Bentley J, Churchman M, Hall J, Taylor CF, Bishop DT, Knowles MA, Kiltie AE (2011). Functional assays to determine the significance of two common XPC 3’UTR variants found in bladder cancer patients. BMC Med Genet 12:84.
Qiao B, Ansari AH, Scott GB, Sak SC, Chambers PA, Elliott F, Vaslin L, Bentley J, Churchman M, Hall J, Taylor CF, Bishop DT, Knowles MA, Kiltie AE (2011) In vitro functional effects of XPC gene rare variants from bladder cancer patients. Carcinogenesis 32:516-521.
Kiemeney L, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson S, Thorleifsson T, Stacey SN, Gudmundsson J, Zanon C, Kostic J, Bjarnason H, Palsson ST, Skarphedinsson OB, Gudjonsson SA, J. Witjes JA, Grotenhuis AJ, Verhaegh GW, Bishop DT, Sak SC, Choudhury A, Elliott F, Barrett JH, Hurst CD, de Verdier PJ, Rudnai P, Gurzau E, Koppova K, Vineis P, Polidoro S, Guarrera S, Sacerdote C, Campagna M, Placidi D, Arici C, Zeegers MP, Kellen E, Gutierrez BS, Sanz-Velez JI, Sanchez-Zalabardo M, Valdivia G, Garcia-Prats MD, Hengstler JG, Blaszkewicz M, Dietrich H, Ophoff RA, van den Berg LH, Alexiusdóttir K, Kristjansson K, Geirsson G, Nikulasson S, Petursdottir V, Kong A, Thorgeirsson T, Mungan NA, Lindblom A, van Es MA, Porru S Buntinx F, Golka K, Mayordomo JI, Kumar R, Matullo M, Steineck G, Kiltie AE, Aben KKH, Jonsson E, Thorsteinsdottir U, Knowles MA, Rafnar T, Stefansson K (2010) A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 42:414-419.
Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa J, Cortessis V, Real FX, Matullo G, Baris D, Thun M, Kiemeney LA, Vineis P, De Vivo I, Albanes D, Purdue MP, Rafnar T, Hildebrandt MAT, Kiltie AE, Cussenot O, Golka K, Kumar R, Taylor JA, Mayordomo JI, Jacobs K, Kogevinas M, Hutchinson A, Wang Z, Fu YP, Prokunina-Olsson L, Burdette L, Yeager M, Wheeler W, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Johnson A, Schwenn M, Karagas M, Schned A, Andriole Jr G, Grubb III R, Black A, Jacobs EJ, Diver RW, Gapstur SM, Weinstein S, Virtamo J, Van Den Berg D, Stern M, Yuan JM, Gago-Dominguez M, Hunter D, McGrath M, Dinney CP, Czerniak B, Chen M, Yang H, Vermeulen SH, Aben KK, Witjes JA, Makkinje RR, Sulem P, Besenbacher S, Stefansson K, Riboli E, Brennan P, Panico S, Navarro C, Allen NE, Bueno-de-Mesquita HB, Trichopoulos D, Caporaso N, Landi MT, Canzian F, Ljungberg B, Tjonneland A, Clavel-Chapelon F, Bishop DT, Teo MTW, Knowles MA, Guarrera S, Polidoro S, Ricceri F, Sacerdote C, Allione A, Cancel-Tassin G, Selinski S, Hengstler JG, Dietrich H, Fletcher T, Rudnai P, Gurzau E, Koppova K, Bolick S, Godfrey A, Xu Z, Sanz-Velez JI, García-Prats MD, Sanchez M, Valdivia G, Porru S, Benhamou S, Hoover RN, Fraumeni JF, Silverman DT, Chanock S (2010) A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 42:978-984.
Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, Seminara D, Yoshida T, Saeki N, Andrew AS, Dinney CP, Czerniak B, Zhang ZF, Kiltie AE, Bishop DT, Vineis P, Porru S, Buntinx F, Kellen E, Zeegers MP, Kumar R, Rudnai P, Gurzau E, Koppova K, Mayordomo JI, Sanchez M, Saez B, Lindblom A, de Verdier P, Steineck G, Mills GB, Schned A, Chang SC, Lin J, Chang DW, Hale KS, Majewski T, Grossman HB, Thorlacius S, Thorsteinsdottir U, Aben KK, Witjes JA, Stefansson K, Amos CI, Karagas MR, Gu J (2009) Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet 41:991-5.
Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, Jakobsdottir M, Helgadottir H, Thorlacius S, Aben KKH, Blöndal T, Thorgeirsson T, Thorleifsson G, Thorisdottir K, Ragnarsson R, Sigurgeirsson B, SkuladottirH, Gudbjartsson T, Isaksson H, Einarsson GV, Benediktsdottir KR, Agnarsson BA, Olafsson K, Salvarsdottir A, Bjarnason H, Asgeirsdotti M, Kristinsson KT, Matthiasdottir S, Sveinsdottir SG, Polidoro S, Höiom V, Botella-Estrada R, Hemminki K, Rudnai P, Bishop DT, Campagna M, Kellen E, Zeegers MP, de Verdier P, Ferrer A, Isla D, Vidal MJ, Andres R, Saez B, Juberias P, Banzo J, Navarrete S, Tres A, Kan D, Lindblom A, Gurzau E, Koppova K, de Vegt F, Schalken JA, van der Heijden HFM, Smit HJ, Termeer RA, Oosterwijk E, van Hooij O, Nagore E, Porru S, Steineck G, Hansson J, Buntinx F, Catalona WJ, Matullo G, Vineis P, Kiltie AE, Mayordomo JI, Kumar R, Kiemeney LA, Frigge M, Jonsson T, Saemundsson H, Barkardotti RB, Jonsson E, Jonsson S, Olafsson JH, Gulcher JR, Masson G, Gudbjartsson D, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants at the TERT- CLPTM1L locus associate with multiple cancer types. Nat Genet 41:221-227.
Choudhury A, Zhao H, Jalali F, Rashid SAL, Ran J, Supiot S, Kiltie AE, Bristow RG (2009) Targeting Homologous Recombination Using Imatinib Results In Enhanced Tumor Cell Chemosensitivity and Radiosensitivity. Mol Cancer Ther 8:203-213.
Bentley J, L’Hote C, Platt F, Hurst CD, Lowery J, Taylor C Harnden P, Sak SC, Knowles MA, Kiltie AE (2009) Papillary and muscle invasive bladder tumors with distinct genomic stability profiles have different DNA repair fidelity and KU DNA-binding activities. Genes Chromosomes and Cancer 48:310-21.
Kiemeney LA, Thorlacius S, Sulem P, Geller G, Aben KKH, Stacey SN, Gudmundsson J, Jakobsdottir M, Bergthorsson JT, Sigurdsson A, Blondal T, Witjes JA, Vermeulen SH, Hulsbergen-van de Kaa CA, Swinkels DW, Ploeg M, Cornel EB, Vergunst H, Thorgeirsson TE, Gudbjartsson D, Gudjonsson SA, Thorleifsson G, Kristinsson KT, Mouy M, Snorradottir S, Placidi D, Campagna M, Arici C, Koppova K, Gurzau E, Rudnai P, Kellen E, Polidoro S, Guarrera S, Sacerdote C, Sanchez M, Saez B, Valdivia G, Ryk C, de Verdier P, Lindblom A, Golka K, Bishop DT, Knowles MA, Nikulasson S, Petursdottir V, Jonsson E, Geirsson G, Kristjansson B, Mayordomo JI, Steineck G, Porru S, Buntinx F, Zeegers MP, Fletcher T, Kumar R, Matullo G, Vineis P, Kiltie AE, Gulcher JR, Thorsteinsdottir U, Kong A, Rafnar T, Stefansson K (2008) Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet 40:1307-1312.
Kotwal S, Choudhury A, Johnston C, Paul AB, Whelan P, Kiltie AE (2008) Similar treatment outcomes for radical surgery and radical radiotherapy in invasive bladder cancer treated in a UK specialist treatment centre. Int J Radiation Oncol Biol Phys 70:456-463.
Diggle CP, Bentley J, Knowles MA, Kiltie AE (2005) Inhibition of double strand break non homologous end joining by cisplatin adducts in human cell extracts. Nucleic Acids Res 33: 2531-2539.
Bentley J, Diggle CP, Harnden P, Knowles MA, Kiltie AE (2004) DNA double strand break repair in human bladder cancer is error prone and involves microhomology associated end joining. Nucleic Acids Res 32:5249-5259.
Diggle CP, Bentley J, Kiltie AE (2003) Development of a rapid, small scale DNA repair assay for use on clinical samples. Nucleic Acids Res 31:e83