Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions

Abstract

The recommended treatment for metastatic urothelial carcinoma (mUC) patients is platinum-based chemotherapy. Although initial response rates are moderate, the vast majority of patients experience a relapse due to chemoresistance and eventually succumb to their disease. Furthermore, platinum-based chemotherapy is toxic and approximately 30% of mUC patients are unfit for chemotherapy. Thus, there is a clear unmet need for novel, more efficacious treatment options in mUC with a safer toxicity profile. To propel the advancement of novel treatment options, we present a summary of key signaling pathways and molecular mechanisms that are known to be involved in bladder cancer tumorigenesis with a focus on promising candidate druggable molecular targets and innovative targeted therapies currently under clinical investigation. Targetable alterations were mainly described in fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (ErbB) tyrosine kinase receptor (RTK) families, downstream pathways, and chromatin remodelers, which are major bladder cancer driver genes. Drugs targeting the FGFR family members are emerging as personalized treatment options for selected mUC patients with tumor-specific FGFR alterations. The pan-FGFR inhibitor, erdafitinib, was first-in-class to receive U.S. Food and Drug Administration (FDA) approval in 2019, while inhibitors of ErbB family members have shown less potential. Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that deliver cytotoxic drugs in close proximity to cancer cells by targeting RTKs or other transmembrane proteins. Enfortumab vedotin is the first-in-class ADC that was FDA approved for the treatment of locally advanced or mUC in 2019.

Identification of a Prognostic Signature Associated With the Homeobox Gene Family for Bladder Cancer

“…Currently, the driver genes of BLCA include ERBB2, HDAC1, PARP1, and mTOR. These genes are important targets in BLCA treatment ( Scholtes et al, 2020 ). We performed correlation analysis between these six genes and BLCA driver genes in the BLCA dataset and found that these six genes have a strong correlation with the driver genes.…”

Prognostic Impact of AHNAK2 Expression in Patients Treated with Radical Cystectomy

“…The poor prognostic value of AHNAK2 in BCa may also result from fibroblast growth factor-1 (FGF1) signaling. The Cancer Genome Atlas (TGCA) project recently indicated that the MAPK/ERK and PI3K/AKT pathways were potential BCa driver genes and that these downstream cascades were mainly activated by FGF receptors (FGFRs), especially FGFR1 and FGFR3 in BCa [ 22 ]. In particular, AHNAK2 is required for non-classical secretion of FGF1, which can universally activate all FGFRs [ 23 , 24 ].…”

“…In fact, these potential relations between AHNAK2 and the MAPK/ERK and PI3K/AKT pathways were reported in lung adenocarcinoma and uveal melanoma [ 12 , 15 ]. Therefore, given the accelerated approval of FGFR inhibitors for patients with advanced BCa by the U.S. Food and Drug Administration, the antitumor effects of a combination of therapies targeting AHNAK2 and FGFRs might be worth analyzing in the future [ 22 ].…”

Cell Therapies in Bladder Cancer Management

“…Novel treatment options for these patients were approved by Food and Drug Administration (FDA) and are currently under clinical investigation. Erdafitinib is a pan-fibroblast growth factor receptor inhibitor that targets this signaling pathway involved in BC tumorogenesis, and enfortumab vedotin is an antibody-drug conjugate (ADC) therapy that recognizes bladder cancer cells to deliver cytotoxic drugs [ 11 ].…”