Advanced Urothelial Carcinoma: Overcoming Treatment Resistance through Novel Treatment Approaches

Abstract

The current standard of care for metastatic urothelial carcinoma is cisplatin-based chemotherapy but treatment is generally not curative. Mechanisms of resistance to conventional cytotoxic regimens include tumor cell drug efflux pumps, intracellular anti-oxidants, and enhanced anti-apoptotic signaling. Blockade of signaling pathways with small molecule tyrosine kinase inhibitors has produced dramatic responses in subsets of other cancers. Multiple potential signaling pathway targets are altered in Urothelial carcinoma (UC). Blockade of the PI3K/Akt/mTOR pathway may prove efficacious because 21% have activating PI3K mutations and another 30% have PTEN inactivation (which leads to activation of this pathway). The fibroblast growth factor receptor 3 protein may be overactive in 50–60% and agents which block this pathway are under development. Blockade of multiple other pathways including HER2 and aurora kinase also have potential efficacy. Anti-angiogenic and immunotherapy strategies are also under development in UC and are discussed in this review. Novel therapeutic approaches are needed in UC. We review the various strategies under investigation and discuss how best to evaluate and optimize their efficacy.

Molecular Profiling of Infiltrating Urothelial Carcinoma of Bladder and Nonbladder Origin

“…Approximately 25% to 30% of the patients with UC present with muscle-infiltrating tumors with substantial potential for further progression, metastases, and death. [3][4][5] Previous molecular studies have shown that UC is characterized by mutations and losses of important cancer genes including Fibroblast growth factor receptor 3 (FGFR3), ras family small GTPase proteins (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), retinoblastoma tumor suppressor protein (RB1), phosophatase and tensin homolog (PTEN), and tumor suppressor protein p53 (TP53). [6][7][8][9] FGFR3 and PIK3CA mutations are more prevalent in low-stage carcinomas, whereas TP53 mutations are more common in muscle-infiltrating UC.…”

Sorafenib induces cathepsin B-mediated apoptosis of bladder cancer cells by regulating the Akt/PTEN pathway. The Akt inhibitor, perifosine, enhances the sorafenib-induced cytotoxicity against bladder cancer cells.

“…Chemotherapy of bladder cancers represents the mainstay of treatment and confers survival advantage. However, despite such advances, it remains disappointing because of its toxicity, reinforcing again the rationale for the discovery of new targeted therapeutic approaches [6]. …”

Involvement of Epigenetics and EMT-Related miRNA in Arsenic-Induced Neoplastic Transformation and Their Potential Clinical Use

“…By candidate gene approach, we identified deregulated expression of some genes involved in MAPK/PI3K/AKT signaling, a pathway that has been implicated even in early stages of urothelial carcinogenesis (33, 34). p-AKT, Cyclin D3, and m-TOR were overexpressed in the arsenic exposed cell lines which is consistent with the previous findings that alterations in these molecules play a notable role in UC oncogenesis (35, 36).…”