A meta-analysis with systematic review: Efficacy and safety of immune checkpoint inhibitors in patients with advanced gastric cancer.

Background: While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC. Methods: A random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan-Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot's algorithm. Results: A pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 (P = 0.02) and PD-L1 ≥10 (P = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H (P <0.00001) and TMB-high (P <0.0001) tumors derived favorable survival benefits from ICIs. Conclusions and relevance: The results of this meta-analysis suggest that ICIs result in improved OS outcomes in aGC. The benefits varied with different ethnicities, class of ICI, PD-L1 expression, MSI status, and TMB. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42019137829).

Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy.

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer.

Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5'-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER+) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER+ breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.