Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α-mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3β phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.
Objective
To evaluate the efficacy and safety of oral vorolanib for the treatment of neovascular (wet) age-related macular degeneration (nAMD).
Methods
In the dose escalation, participants received ascending doses of oral vorolanib (25–100 mg daily). In the dose expansion, participants received recommended doses (25 and 50 mg daily).
Results
Between March 15, 2015, and January 23, 2019, 41 participants were enrolled in 6 centres in China. At the data cut-off (November 14, 2019), two dose-limiting toxicities (DLTs) were observed during dose escalation (one in the 75 mg cohort and one in the 100 mg cohort). The maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 33 (80.5%) participants, and grade 3 or higher TRAEs occurred in 12 (29.3%) participants. No fatal TRAEs were observed. Increases in the mean best-corrected visual acuity (BCVA) from baseline to Day 360 of +7.7 letters (range, −5–29; n = 41) were observed in participants who were administered vorolanib. Corresponding reductions in mean central subfield thickness (CST) and choroidal neovascularization (CNV) area at Day 360 were observed in these three groups.
Conclusions
Oral administration of vorolanib improved visual outcomes in participants with nAMD with manageable systemic safety profiles.
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