Gurung, PMS; (2015) The role of AIMP3, a putative tumour suppressor gene, as a predictive biomarker of response to chemo/radiotherapy in vitro and in patients with muscle-invasive bladder cancer. Doctoral thesis , UCL (University College London).

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Abstract

Bladder cancer is the second most common urological cancer after prostate cancer and is one of the leading causes of cancer mortality in most western countries. For organ-confined, muscle-invasive disease, the standard of care, in terms of definitive cure, remains radical surgery (cystectomy) with lymphadenectomy. However, survival rates remain poor following supposedly curative treatment. Radical radiotherapy and more recently, multimodality treatment incorporating chemo-radiotherapy, are alternatives which allow bladder preservation in those choosing not to undergo or are unsuitable for radical surgery. However, survival rates following radiotherapy are generally lower relative to radical cystectomy and multimodality treatments can only be offered to select cases in few institutions. Biomarkers which can accurately predict tumour response to radiotherapy or chemotherapy can aid the selection of patients who are likely to respond well to treatment options incorporating radiotherapy and/or chemotherapy, as alternatives to radical cystectomy, in the management of bladder cancer. Such a strategy would allow personalised cancer care with patients likely to benefit from treatments that they are likely to respond well to and concomitantly avoid complications arising from other treatments less likely to benefit them. This thesis investigated the novel tumour suppressor gene, AIMP3 which is involved in the DNA damage response (DDR) pathway following exposure to genotoxic insults such as irradiation and chemotherapy. The expression and cellular localisation of AIMP3 protein was characterised in a panel of bladder cancer cell lines. Expression of AIMP3 was altered by gene knockdown with siRNA transfection and survival outcomes assessed following irradiation and chemotherapy. The predictive value of AIMP3 expression in determining survival outcome of patients with muscle-invasive bladder cancer who had undergone radical radiotherapy, with or without carbogen supplementation, in the BCON trial, was assessed. Prognostic significance was evaluated by interrogating a control cohort of patients who had undergone radical cystectomy and had not had exposure to radiotherapy or either neoadjuvant or adjuvant chemotherapy. Reportedly important DDR proteins, including Mre11, p53 and ERCC1, were also interrogated in the BCON, Radical Cystectomy, Neodjuvant and LaMB trial TMA datasets. Clonogenic survival outcomes following AIMP3 knockdown were also investigated in cisplatin-sensitive (RT112) and cisplatin-resistant (RT112CP) cell lines following cisplatin exposure. Survival outcome, stratified for AIMP3 as well as ERCC1, Mre11 and p53 status, were interrogated in the Neoadjuvant set, which incorporated a cohort of patients who had undergone cisplatin-based neoadjuvant chemotherapy prior to radical treatment. This was validated in a second cohort of patients who had undergone cisplatin-based chemotherapy as part of the LaMB trial.

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