Cytotoxic and DNA‐targeted therapy in urothelial cancer: Have we squeezed the lemon enough?

Abstract

Urothelial cancer has long been known as a chemotherapy‐sensitive disease. However, clinical trial data to date suggest a plateau to the magnitude of benefit from cytotoxic therapy alone. In spite of level 1 evidence supporting cisplatin‐based chemotherapy for patients with muscle‐invasive and metastatic urothelial cancer, underuse prevails among patients with localized disease and only a modest survival benefit exists in the metastatic setting, although trials have consistently demonstrated that there is a subset of patients who clearly benefit. Recent comprehensive genomic profiling has identified a high prevalence of actionable genomic alterations as well as other potential targets yet to be fully understood. Modern clinical trials must now focus on identifying predictive biomarkers to select those patients who will benefit most from cytotoxic chemotherapy, molecularly targeted therapy, or potentially both. Cancer 2015;121:179–87. © 2014 American Cancer Society.

Targeting glycogen metabolism in bladder cancer

“…86 Furthermore, downstream glycolytic inhibitors, such as lonidamine, 3-bromopyruvate and 2-deoxy-D-glucose, negatively regulated tumour growth by preventing the activity of the glycolytic enzyme hexokinase. 87,88 Combination of 2-deoxy-D-glucose with anticancer drugs adriamycin, paclitaxel or daunorubicin (three chemotherapeutics already used to treat urological cancers, however, with variable success) 89 resulted in increased therapeutic sensitivity in osteosarcoma, non-small-cell lung cancer, and leukaemia cell lines through an increase in cell death in vitro and a decrease in tumour growth in xenografts. 83,88,90 These combination therapies have not been tested in either urological cancers or specifically in cancers with abnormal glycogen metabolism, which is where we propose they would be most effective.…”

The clinical significance of HER2 protein amplification/expression in urinary bladder lesion

“…The recurrence rate after cystectomy approaches 50%, indicating that this treatment alone might not be optimal for some patients [4] . Targeted therapy is a novel treatment strategy in oncology, targeting specific signalling pathways within the malignant cells, and that might enhance the cytotoxic effect but with fewer adverse events [5] .…”

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer

“…Specific molecular alterations included those involved in the RTK/Ras/PI(3)K, cell-cycle regulation and chromatin-remodeling pathways. For example, common alterations included PIK3CA and AKT3 in the PI(3)K/AKT/mTOR pathway and FGFR3 and ERBB2 in the RTK/RAS pathway, all of which have either targeted therapies approved or under investigation [27]. In one published report, a patient with metastatic UCB progressed after 4 cycles of MVAC and showed further progression following salvage chemotherapy with two cytotoxic regimens [28].…”