Review article
Targeted therapies in non-muscle-invasive bladder cancer according to the signaling pathways

https://doi.org/10.1016/j.urolonc.2009.07.025Get rights and content

Abstract

With 300,000 annually new cases worldwide, urothelial-cell carcinoma of the bladder (UCCB) is the second most common urologic neoplasm after prostate carcinoma. Non-muscle-invasive bladder cancer (NMIBC), which is not immediately life-threatening, represents 70% to 80% of these initial cases. Despite optimal treatment (transurethral resection with intravesical chemo- or immunotherapy), 70% of these NMIBC will recur, and 10% to 20% will progress, highlighting the need for a new therapeutic approach. Indeed, the identification of patients at high risk of disease recurrence and progression would be beneficial in predicting which patients with NMIBC would benefit from strict follow-up and which would benefit from a more aggressive therapy. To date, conventional treatment remains disappointing in terms of oncologic results and morbidity. The growing understanding in tumor biology has enabled the signaling pathways involved in bladder tumorigenesis and progression to be identified, but few molecular targets have been available until now. The encouraging results seen in various human carcinomas suggests that these new agents should become part of the arsenal of drugs available in the treatment of NMIBC, alone or in combination with already known agents. In this article, we have tried to highlight the main molecular signaling pathways involved in NMIBC tumorigenesis and progression, and the potential targets useful for improving the treatment of NMIBC.

Introduction

Each year, more than 300,000 new cases of urothelial-cell carcinoma of the bladder (UCCB) occur worldwide, indicating a critical international public health problem [1]. Approximately 70% to 80% of UCCB are non-muscle-invasive bladder cancers (NMIBCs), including 70% pTa, 20% pT1, and 10% carcinoma in situ (Cis), all of which do not invade the basement membrane [2]. The remaining 20% to 30% of UCCBs are muscle invasive (MIBC) from the outset, with a poor clinical outcome of less than 50% survival at 5 years [3], [4]. Almost 70% of NMIBCs recur even after optimal therapy (transurethral resection with intravesical chemotherapy [mitomycin] or immunotherapy [BCG]), and 10% to 20% will progress to a higher stage and/or grade, especially the high-risk pT1 high grade UCCB group [1], [5]. Despite significant improvements, NMIBC treatment remains disappointing in terms of oncologic results and morbidity. Indeed, NMIBC is characterized by economic impact (high rate of recurrence) and not by mortality, contrary to MIBC [6]. The most striking feature is that similar histopathologic UCCB may have a different clinical outcome, which probably reflects the diversity of molecular pathway alterations involved in bladder tumorigenesis and progression, and justifies the rationale for developing targeted therapy. The use of targeted treatment has the advantage of improving tolerance and also efficacy by attacking the cancer cells only. It may provide, in the near future, an additional efficient therapy.

Section snippets

Molecular characteristics of NMIBC tumorigenesis (Fig. 1)

Multiple altered molecular pathways are specifically involved in the development of NMIBC, suggesting a multiplicity of potential targets for the development of new therapeutic strategies. Cancer research has shown that NMIBC results from genetic and epigenetic abnormalities, which deregulate critical molecular pathways involved in cellular homeostasis. Some of the alterations take place very early in tumorigenesis, such as DNA repair mechanisms, reflecting the “addiction of tumors to certain

General molecular features

The tyrosine kinase receptor (RTK) family includes epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), which play a critical role in cellular growth, differentiation, adhesion, mobility, and apoptosis [8]. Activation of these RTKs by mutation or gene over-expression may lead to tumorigenesis.

Targeted therapy in NMIBC

Because the limits of current therapy in NMIBC (transurethral bladder tumor resection with chemo- or immunotherapy) have been reached, new approaches are urgently needed. The major issue in NMIBC is prediction of recurrence and progression by using biomarkers that could be potentially targeted in emerging therapies. Despite scientific advances, the potential application of targeted treatment is only just beginning in a few clinical trials and, unfortunately, is not yet ready for common clinical

Conclusion

The natural history of NMIBC is difficult to predict because of tumor heterogeneity. Although molecular markers do not have significant clinical application in treating UCCB at present, their use for predicting more aggressive tumors and influencing therapeutic decision is likely to be seen in the near future. A combination of various markers rather than a single agent will be more efficient in cancer diagnosis and prognosis. The new approaches using DNA micro-array or proteomic techniques,

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