The development of pre-clinical models to study and identify novel biomarkers in muscle invasive bladder cancer
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Bladder cancer is the 4th commonest malignancy in the United Kingdom and worldwide there are nearly 400,000 new cases every year with over 150,000 deaths. The gold standard treatment for muscle invasive bladder cancer is radical cystectomy with neoadjuvant chemotherapy. Despite this the overall survival at 5 years is only around 50%. To improve outcomes new pre-clinical models of greater physiological relevance are needed and the ability to translate research from the laboratory to clinical practice needs to be improved. The tyrosine kinase HER2 is an attractive therapeutic target in bladder cancer and has the potential to be used in clinical practice. The hypothesis of this thesis was that HER2 would be a prognostic biomarker in patients with bladder cancer requiring radical cystectomy and that it has a critical role in bladder cancer cell invasiveness. To test this the aims were firstly to create a novel three dimensional cell culture to be used as a more physiological method of studying the invasiveness of bladder cancer. Secondly a tissue micro-array and associated database of cystectomy patients was created for biomarker discovery and to investigate the role of HER2 and its family members as biomarkers in patients with bladder cancer treated with cystectomy. The novel three dimensional organotypic model was successfully optimized and its ability to reproduce invasive characteristics confirmed with primary invasive cancer cells harvested from a cystectomy patient. Lenti-viral knockdown of HER2 failed to affect the invasive nature of the T24 cell line. The TMA consisted of 226 cystectomy patients treated over a 10-year period with a median follow up of 49 months. The 5-year overall survival was 48.8% with a cancer specific survival of 62.1% and 27.4% of patients received neo-adjuvant chemotherapy. 17% of patients overexpressed HER2 and HER2 was an independent risk factor for worse overall survival with a hazard ratio of 1.66. Other biomarkers screened for included Nrf-2, which this TMA suggests predicts response to cisplatin based chemotherapy, AIMP3 which may predict resistance to radiation when down regulated and b-HCG, which demonstrated a potential role as a marker of recurrence when measured in blood serum. In conclusion, HER2 appears to be prognostic of poor outcome in this cohort but is not critical for bladder cancer invasion in the organotypic model. The process of testing this has created two valuable models for biomarker discovery that will be used in future research.Keywords:
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Locally advanced, muscle-invasive urothelial carcinoma of the bladder (MIBC) may be definitively treated with either radiotherapy or radical cystectomy (RC) with urinary diversion. Neoadjuvant chemotherapy (NAC) is typically administered prior to treatment with either modality. Receiving NAC prior to RC might confer a survival advantage compared to undergoing RC alone. However, its usefulness has been questioned due to concerns about over treatment and toxicity. Having the ability to predict whether individual patients would benefit from or be harmed by NAC would be an important tool in precision medicine. Unfortunately, to date no prognostic or predictive molecular markers have been validated for this purpose. In this manuscript, we review the current state of molecular markers in MIBC treatment and outline how recent advances in whole-genome sequencing may soon improve the selection of precisely targeted therapeutics for the benefit of individual patients.
Neoadjuvant Therapy
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Abstract: Radical cystectomy (RC) is the standard of care treatment of localized muscle-invasive bladder cancer (BC). However, about 50% of patients develop metastases within 2 years after cystectomy. Neoadjuvant cisplatin-based chemotherapy before cystectomy improves the overall survival (OS) in patients with muscle-invasive BC. Pathological response to neoadjuvant treatment is a strong predictor of better disease-specific survival. Nevertheless, some patients do not benefit from chemotherapy. The identification of reliable biomarkers enabling clinicians to identify patients who might benefit from chemotherapy is a very important clinical task. An identification tool could lead to individualized therapy, optimizing response rates. In addition, unnecessary treatment with chemotherapy which potentially leads to a loss of quality of life and which might also might cause a delay of cystectomy in a neoadjuvant setting could be avoided. The present review aims to summarize and discuss the current literature on biomarkers for the prediction of response to systemic therapy in muscle-invasive BC. Tremendous efforts in genetic and molecular characterization have led to the identification of predictive candidate biomarkers in urothelial carcinoma (UC), although prospective validation is pending. Ongoing clinical trials examining the benefit of individual therapies in UC of the bladder (UCB) by molecular patient selection hold promise to shed light on this question.
Neoadjuvant Therapy
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The current standard treatment for muscle-invasive nonmetastatic bladder cancer is neoadjuvant platinum-based chemotherapy followed by radical cystectomy. However, neoadjuvant chemotherapy is not widely accepted even with level 1 evidence. Adjuvant chemotherapy should be discussed if patients have not received neoadjuvant chemotherapy before surgery and have high-risk pathologic features. Although not considered standard of care, bladder-sparing therapy can be considered for highly selected patients and for those medically unfit for surgery. Even though there are no level 1 data, the treatment outcomes for highly select patients given bladder-sparing therapy appear promising, with many patients retaining a functional bladder. Personalized chemotherapy is currently being actively pursued to target the underlying molecular changes and tailor to individual needs.
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Neoadjuvant Therapy
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Neoadjuvant Therapy
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Bladder cancer is a major cause of morbidity and mortality. At initial diagnosis, 75% of patients present with nonmuscle-invasive disease and 25% of patients have muscle-invasive or metastatic disease.Patients with noninvasive disease suffer from a high rate of recurrence and 10–30% will have disease progression. Patients with muscle-invasive disease are primarily treated with radical cystectomy, but frequently succumb to their disease despite improvements in surgical technique. In non–muscle-invasive disease, multiplicity, tumor size, and prior recurrence rates are the most important predictors for recurrence, while tumor grade, stage, and carcinoma in situ are the most important predictors for progression. The most common tool that clinicians use to predict outcomes after radical cystectomy is still the tumor-node-metastasis (TNM) staging system, with lymph node involvement representing the most important prognostic factor. However, the predictive accuracy of staging and grading systems are limited, and nomograms incorporating clinical and pathologic factors can improve prediction of bladder cancer outcomes. One limitation of current staging is the fact that tumors of a similar stage and grade can have significantly different biology. The integration of molecular markers, especially in a panel approach, has the potential to further improve the accuracy of predictive models and may also identify targets for therapeutic intervention or patients who will respond to systemic therapies.
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Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.
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Current guidelines recommend cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy as the preferred treatment of muscle-invasive bladder cancer. Nevertheless, for multiple reasons compliance with this guideline recommendation is low. This is particularly evident in clinical T2 bladder cancer, where controversy exists regarding the role of proceeding with radical cystectomy alone. Novel biomarkers such as molecular phenotype and DNA damage repair and response gene alterations may be able to predict who will respond to cisplatin-based neoadjuvant chemotherapy. This clinical problem is discussed, and a recommendation is made given the current state of the art. PATIENT SUMMARY: Neoadjuvant chemotherapy improves survival for patients with muscle-invasive bladder cancer. In the future, perhaps validated biomarkers may predict who should and should not receive this treatment.
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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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