Novel Molecular Targets for the Therapy of Urothelial Cancer.

First-line platinum-based chemotherapy combinations are considered standard-of-care in locally advanced and metastatic urothelial cancer. However, long-term outcomes, including disease-specific and overall survival, remain poor. In addition, a number of patients with advanced urothelial carcinoma have co-existing medical issues that preclude the use of conventional chemotherapy. Improvements in our understanding over the molecular mechanisms of urothelial cancer have led to first-generation clinical trials evaluating novel agents targeting molecular pathways that may be relevant, at least in sub-populations. Emerging information regarding outcome with agents targeting novel molecular targets in advanced urothelial cancer is discussed in this review.

Novel molecular targets for the therapy of urothelial carcinoma.

INTRODUCTION: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 - 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual. AREAS COVERED: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review. EXPERT OPINION: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.