Elevating the Horizon: Emerging Molecular and Genomic Targets in the Treatment of Advanced Urothelial Carcinoma

Abstract

Despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in vitro, patients with advanced urothelial carcinomas continue to have poor clinical outcomes. In the present review, we focus on targeted therapies that have yielded the most promising results alone or combined with traditional chemotherapy, including the antiangiogenesis agent bevacizumab, the human epidermal growth factor receptor 2 antibody trastuzumab, and the tyrosine kinase inhibitor cabozantinib. We also describe ongoing and developing clinical trials that use innovative approaches, including dose-dense scheduling of singular chemotherapy combinations, prospective screening of tumor tissues for mutational targets and biomarkers to predict chemosensitivity before the determination of the therapeutic regimen, and novel agents that target proteins in the immune checkpoint regulation pathway (programmed cell death protein 1 [PD-1] and anti-PD-ligand 1) that have shown significant potential in preclinical models and early clinical trials. New agents and targeted therapies, alone or combined with traditional chemotherapy, will only be validated through accrual to developing clinical trials that aim to translate these therapies into individualized treatments and improved survival rates in urothelial carcinoma.

Keywords: Bladder cancer; Clinical trials; Immune checkpoints; Novel agents; Targeted therapy.

Figure 1

Schematic of chosen therapy for patients on MATCH-UP trial. Genetic testing of tumor sample is utilized to match patients to treatments that target tumor molecular abnormalities. Abbreviations: PTEN, phosphatase and tensin homolog; HAT, histone acetyltransferase-like protein; CDK 4/6, cyclin-dependent kinase 4/6; HER2, human epidermal growth factor receptor 2; HDAC, histone deacetylase.

Figure 2

Randomization of patients to treatment arms in ATLANTIS trial. Tumor tissue is prospectively screened for clinically relevant biomarkers to identify patients who could potentially benefit from maintenance therapy following 4 to 8 cycles of first-line chemotherapy.

Figure 3

Study design of COXEN algorithm to investigate tumor tissue biomarkers as a means to predict chemosensitivity and select “best next therapy” for individual patients with platinum-refractory metastatic bladder cancer.