Temsirolimus as a dual inhibitor of retinoblastoma and angiogenesis via targeting mTOR signalling.

Targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. Temsirolimus, a FDA-approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies, is a potent mTOR inhibitor. In this work, we are the first to provide preclinical evidence that temsirolimus is an attractive candidate for retinoblastoma treatment as a dual inhibitor of retinoblastoma and angiogenesis. We show that temsirolimus selectively inhibits growth, survival and migration of retinoblastoma cells while sparing normal retinal and fibroblast cells, with IC value that is within the clinically achievable range. Temsirolimus potently inhibits retinal angiogenesis via targeting biological functions of retinal endothelial cells. Our mechanism analysis demonstrates that temsirolimus inhibits retinoblastoma and angiogenesis via suppressing mTOR signalling and secretion of proangiogenic cytokines. In line with in vitro data, we further demonstrate the inhibitory effects of temsirolimus on retinoblastoma and angiogenesis in in vivo xenograft mouse model. Our findings provide a preclinical rationale to explore temsirolimus as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.