Research in Dr Kiltie's laboratory focuses on the investigation of DNA damage signalling and DNA repair and the role they play in causing bladder cancer, as well as their role in how the cancer responds to radiotherapy and combined modality treatments.

Dr Anne Kiltie

Research Summary

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). Both NHEJ and MMEJ are 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 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.

 

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 and to establish the role of other such biomarkers, in collaboration with the Paterson Institute in Manchester, Leeds Institute of Molecular Medicine and the University of Birmingham. As part of the validation process, potential biomarkers will be 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.

 

DNA repair genes identifying individuals at high risk of bladder cancer

DNA damage caused by environmental factors often leads to modification of the bases within the DNA helix. Modified bases can form irregular chemical bonds and so-called bulky adducts. Repair of bulky adducts is through nucleotide excision repair (NER) and earlier studies in germ-line DNA from bladder cancer patients revealed rare variants in the NER gene XPC. Research is now ongoing to establish which DNA repair gene germ-line variants implicated in bladder cancer risk would allow identification of high-risk individuals, who would benefit from prophylactic intervention with targeted screening and lifestyle intervention to minimize bladder cancer mortality.

 

Key trials

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) is a prospective observational feasibility study that will test 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.

 

RADICALS is a large phase III randomised controlled clinical trial which aims to determine the optimal timing of radiotherapy and duration of hormone therapy in men who have had surgery (radical prostatectomy) for prostate cancer. The trial aims to include around 3,000 participants and Oxford is one of the recruiting centres.

Biography

Projects

Currently available DPhil projects:

• Development of micro-irradiation and imaging methods in bladder tumour modes. Supervisors: Dr Anne Kiltie & Dr Sean Smart (REF: RB13AK2)