Urinary biomarkers and integrated genomics in bladder cancer

Abstract

© 2015 Dr. Nikhil SapreMuch remains to be elucidated regarding the molecular mechanisms driving urothelial carcinoma of the bladder (CaB). While comprehensive molecular analyses of several other cancers such as melanoma and breast cancer have led to the development of targeted therapies that have fundamentally changed treatment paradigms, there has been little progress in CaB in this arena. As a result, CaB outcomes have not improved in over three decades. Despite extensive efforts, a sensitive and specific non-invasive marker for CaB remains elusive. CaB diagnosis and surveillance are reliant on imaging and invasive procedures such as cystoscopy. Consequently, it is the single most expensive cancer to manage per incident case from diagnosis to death. After reviewing the molecular pathways and the landscape of urinary biomarker profiling in CaB, this thesis highlights the move towards profiling of genomic urinary biomarkers over proteomic and cell-based biomarkers and emphasises the need for a comprehensive and integrated approach to molecular profiling of CaB. It focuses on the role of genomic urinary biomarkers in surveillance of bladder cancer as well as comprehensive genetic and epigenetic profiling of CaB. The establishment of a robust platform for translational research and clinical trials in CaB in the setting of a novel bladder cancer clinical service is presented in these studies. The ability of CaB to recur over a long period of time and the impact of prolonged surveillance protocols on the quality of life of CaB patients further highlights the need for urgent development of clinically useful urinary and tissue biomarkers to predict disease behaviour in what is a very heterogeneous cancer. The integrated CaB service and its use as a platform for fast-tracking such translational studies is highlighted, bridging the gap from bench to bedside. The development and validation of a urinary microRNA signature for the detection of CaB recurrence during surveillance is presented. This thesis presents the outcomes of the first clinical trial of a new commercial mRNA-based urinary test uRNA-2 (Cxbladder) in the surveillance of CaB and highlights the challenges in integrating urinary biomarkers in the clinical management of CaB. Also highlighted are important genes and pathways across the progressive spectrum of CaB, both validating several aspects of current models and drawing attention to novel pathways. The value of a multidimensional analysis is evident when epigenetically driven changes in gene expression are identified and validated. In summary, this thesis reports the establishment of a bladder cancer biorepository with clinically annotated tissues and the subsequent use of this platform for development and validation of urinary biomarkers in CaB and a comprehensive molecular analysis of CaB. These studies represent an important step towards use of urinary and tissue biomarkers to predict bladder cancer behaviour and their use in a clinical setting