Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives

Abstract

Background: Chemotherapy is a first-line treatment for advanced and metastatic bladder cancer, but the unsatisfactory objective response rate to this treatment yields poor 5-year patient survival. Only PD-1/PD-L1-based immune checkpoint inhibitors, FGFR3 inhibitors and antibody-drug conjugates are approved by the FDA to be used in bladder cancer, mainly for platinum-refractory or platinum-ineligible locally advanced or metastatic urothelial carcinoma. Emerging studies indicate that the combination of targeted therapy and chemotherapy shows better efficacy than targeted therapy or chemotherapy alone. Newly identified targets in cancer cells and various functions of the tumour microenvironment have spawned novel agents and regimens, which give impetus to sensitizing chemotherapy in the bladder cancer setting.

Aim of review: This review aims to present the current evidence for potentiating the efficacy of chemotherapy in bladder cancer. We focus on combining chemotherapy with other treatments as follows: targeted therapy, including immunotherapy and antibody-drug conjugates in clinic; novel targeted drugs and nanoparticles in preclinical models and potential targets that may contribute to chemosensitivity in future clinical practice. The prospect of precision therapy is also discussed in bladder cancer.

Key scientific concepts of review: Combining chemotherapy drugs with immune checkpoint inhibitors, antibody-drug conjugates and VEGF inhibitors potentially elevates the response rate and survival. Novel targets, including cancer stem cells, DNA damage repair, antiapoptosis, drug metabolism and the tumour microenvironment, contribute to chemosensitization. Gene alteration-based drug selection and patient-derived xenograft- and organoid-based drug validation are the future for precision therapy.

Keywords: Antibody-drug conjugate; Cancer stem cell; Immune checkpoint inhibitor; Organoid; Targeted therapy; Tumour microenvironment.

Graphical abstract

Fig. 1

Cancer stem cells contribute to chemosensitization of bladder cancer in preclinical studies. HSP90, heat shock protein 90; PDGFR, platelet-derived growth factor receptor; PDGF-B, platelet-derived growth factor-B; PDGF-BB, platelet-derived growth factor-B dimer; YAP, yes-associated protein; TEAD, TEA domain transcription factor.

Fig. 2

Promising targets and pathways that improve the chemotherapy efficacy of bladder cancer in preclinical studies. ARA, arachidonic acid; COX-2, cyclooxygenase-2; CYPE, cytochrome P450 epoxygenase; PGE₂, prostaglandin E₂; EET, epoxyeicosatrienoic acid; sEH, soluble epoxide hydrolase; CK1δ, casein kinase 1 delta; dCK, deoxycytidine kinase; PARP, poly(adenosine diphosphate [ADP]) ribose polymerases; WDR5, WD repeat domain 5; H3K4me3, trimethylation of lysine 4 on histone H3 protein subunit; EGFR, epithelial growth factor receptor; CEBPD, CCAAT/enhancer-binding protein delta; AR, androgen receptor.

Fig. 3

Targets and pathways that potentially sensitize bladder cancer patients to chemotherapy in experimental studies. CSC, cancer stem cell; CAFs, cancer-associated fibroblasts; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; ERβ, oestrogen receptor beta; Maspin, mammary serine protease inhibitor; FGF9, fibroblast growth factor 9; FGFR3c, fibroblast growth factor 3c; hnRNPK, heterogeneous nuclear ribonucleoprotein K; TACC3, transforming acidic coiled-coil protein 3; CHK1, checkpoint kinase 1.

Fig. 4

Prospect of precision chemotherapy and targeted therapy for bladder cancer.