PD-1/L1 inhibitors can improve but not replace chemotherapy for advanced urothelial carcinoma:A systematic review and network meta-analysis

Background:Programmed cell death-1/ligand 1 inhibitors are a new treatment strategy for advanced urothelial carcinoma.Therefore,a comparative evaluation of their efficacy and toxicity compared with chemotherapy is necessary.Methods:We comprehensively searched PubMed,Web of Science,Embase,and Cochrane Library databases and performed a meta-analysis of randomized controlled trials up to July 2021.We considered overall survival as the primary outcome,and progression-free survival,objective response rate,and treatment-related adverse events as secondary outcomes.Results:Overall,3584 patients from five studies were evaluated.Compared with first-line chemotherapy,programmed cell death-1/ligand 1 inhibitors were significantly associated with worse progression-free survival(p<0.001)and adverse objective response rates(p<0.001).However,the treatments were not significantly different in terms of overall survival(p=0.33).Compared with second-line chemotherapy,programmed cell death-1/ligand 1 inhibitors significantly improved overall survival(p<0.001),and there was no statistically significant difference in progression-free survival(p=0.89)or objective response rate(p=0.34).Compared with chemotherapy,programmed cell death-1/ligand 1 inhibitors were well tolerated(first-line chemotherapy:p<0.001;second-line chemotherapy:p<0.001).Conclusions:The efficacy of programmed cell death-1/ligand 1 inhibitors in patients with advanced urothelial carcinoma is not superior to that of first-line platinum-based chemotherapy but is better than second-line chemotherapy;however,programmed cell death-1/ligand 1 inhibitors are safer than first-and second-line chemotherapy and have a broader prospect for use in combination therapy.

HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program

Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options.Emerging evidence shows that heat shock factor 1(HSF1)drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target.However,the roles of HSF1 in lymphatic metastasis remain largely unknown.Herein,we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential.Methods:We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors(HSFs)and heat shock proteins(HSPs),and analyzed its clinical relevance in three cohorts.Functional in vitro and in vivo assays were performed in HSF1-silenced and-regained models.We also used Coimmunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual-luciferase reporter assays to investigate the transcriptional program directed by HSF1.The pharmacological inhibitor of HSF1,KRIBB11,was evaluated in popliteal lymph node metastasis models and patientderived xenograft models of bladder cancer.Results:HSF1 expression was positively associated with lymphatic metastasis status,tumor stage,advanced grade,and poor prognosis of bladder cancer.Importantly,HSF1 enhanced the epithelial-mesenchymal transition(EMT)of cancer cells in primary tumor to initiate metastasis,proliferation of cancer cells in lymph nodes,and macrophages infiltration to facilitate multistep lymphatic metastasis.Mechanistically,HSF1 interacted with protein arginine methyltransferase 5(PRMT5)and jointly induced the monomethylation of histone H3 at arginine 2(H3R2me1)and symmetric dimethylation of histone H3 at arginine 2(H3R2me2s).This recruited the WD repeat domain 5(WDR5)/mixed-lineage leukemia(MLL)complex to increase the trimethylation of histone H3 at lysine 4(H3K4me3);resulting in upregulation of lymphoid enhancer-binding factor 1(LEF1),matrix metallopeptidase 9(MMP9),C-C motif chemokine ligand 20(CCL20),and E2F transcription factor 2(E2F2).Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity.Conclusion:Our findings reveal a novel transcriptional program directed by the HSF1-PRMT5-WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer.Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis.