Novel Combination Therapies for the Treatment of Bladder Cancer

Abstract

Bladder cancer is the ninth most frequently diagnosed cancer world-wide and ranks 13th in cancer-related deaths. Two tremendous breakthroughs in bladder cancer therapy over the last decades are the approval of immune checkpoint inhibitors(ICIs)and the fibroblast growth factor receptor tyrosine kinase inhibitor (FGFR-TKI) erdafitinib for treating this deadly disease. Despite the beneficial effects of these approaches, the low response rate and the potential resistance of the cancer are major concerns. Hence, novel combination therapies to overcome these limitations have been investigated. In this context, combining immunotherapy with targeted drugs is an appealing therapeutic option to improve response and reduce the emergence of resistance in the management of bladder cancer. In this review, the rationale of using different therapeutic combinations is discussed according to the mechanistic differences, emphasizing the efficacy and safety based on evidence collected from preclinical and clinical studies. Finally, we highlight the limitations of these combinations and provide suggestions for further efforts in this challenging field.

Is Curcumin the Answer to Future Chemotherapy Cocktail?

“…These drawbacks could be alleviated by co-administering curcumin, such that a lower dosage of therapeutic agents is required. Thus, this could reduce the toxicity and adverse effects encountered by patients, besides yielding a significant therapeutic response [ 6 , 64 ]. To date, numerous preclinical investigations involving in vitro, in vivo and ex vivo studies have been conducted on the use of curcumin in combination therapy in various cancers ( Table 1 ).…”

“…Compared to conventional single-agent therapies, combination therapy exhibits numerous benefits, such as targeting multiple oncogenic pathways, reducing high toxicity levels implicated by monotherapy, improving the magnitude of therapeutic responses and reducing the likelihood of therapeutic resistance [ 5 ]. These benefits allow for the greater suppression of cancer cells and reduce the risk of cancer recurrence, thus improving the patient’s quality of life [ 4 , 6 ]. Lately, curcumin has gained a great deal of interest, attributed to its broad range of medicinal properties [ 7 ].…”

“…Intriguingly, curcumin exhibited countless anticancer properties, such as limiting cancer cell proliferation, promoting tumor cell death and preventing metastasis [ 7 , 8 ]. Besides, curcumin supplementation greatly relieves the patients from experiencing adverse effects caused by conventional therapies [ 6 ]. Hence, these properties pose great advantages to the development of curcumin combination therapy for cancer treatment.…”

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

“…FGFRis reduce phosphorylation of FGFRs directly and indirectly via their targets, FRS2 and PLC-γ, and inactivate downstream signaling via RAS-ERK, PI3K-AKT, IP3-Ca2+, and DAG-PKC signaling cascades [4,5,8,17,[23][24][25][26]30,[38][39][40][41][42]. In the TME of a/m UBC, the luminal-papillary subtype of the consensus classification is characterized by a high rate of FGFR3 mutations and translocations, suggesting that these tumors may respond to FGFRi [4,5,8,15,17,18,37].…”

“…Moreover, the FGFR3 pathway is activated in non-T-cell-inflamed tumors, which are likely to be intrinsically resistant to ICIs. FGFRi elicits antitumor effects directly in cancer cells by suppressing tumor cell survival, epithelialmesenchymal transition (EMT), invasion, metastasis, and the development of treatment resistance, as well as indirectly through the normalization of the TME, especially paracrine signaling, angiogenesis, and immune evasion (Figure 2) [4,5,8,11,15,17,18,[23][24][25][26]30,[37][38][39][40][41][42][43][44][45].…”