As a generic mediator of stress, the ASMase/ceramide pathway has been shown to function on trans-activating pathogenesis of tissue damage in multiple models of human disease . Endothelial cells are particularly sensitive to SDRT-induced apoptosis in vitro and in vivo because they have 20-fold higher levels of secretory ASMase relative to other mammalian cells [5, 10, 35]. Our results showed that SDRT launched ASMase activity in vivo and in vitro, which resulted in a significant increase in endothelial cell apoptosis via enhanced ceramide generation. Although the detailed mechanism by which radiation-induced translocation/activation of ASMase was not addressed here, the accumulated information over the last decade sheds light on this event. Diverse stresses (UV, IR etc) induce ASMase trafficking to the outer leaflet of the plasma membrane, where it converts sphingomyelin to ceramide [9, 36]. This process requires intact microtubules, phosphorylation of Ser508 of ASMase, as well as functional lipid rafts [37–39]. However, the mechanism by which VEGF may repress ASMase activity remains unclear. What is becoming clear from this and our other most recent studies (14) is that anti-VEGF pathway inhibitors synergistically increased SDRT-induced ASMase activity by reversing the effect of VEGF. In addition, several publications revealed that upregulation of ASMase occurred in diverse pathological conditions, and proposed that a significant change of serum ASMase may appear as a novel biomarker in disease [40, 41]. Sathishkumar et al. showed that serum ASMase activity and ceramide content increase following Spatially Fractionated high dose Radiation Treatment (SFGRT)  and correlate with the clinical response . Here we also showed that SDRT promoted an increase of ASMase activity in mouse serum at 1 h and maintained high level at 6 h post-SDRT, and an anti-VEGF agent synergistically increased this activity. These results indicate that the changes of ASMase activity can serve as a biomarker when monitoring the delivery of SDRT to cancer patients. We have already confirmed this concept in patients in ongoing clinical trials at MSKCC (Campagne and Fuks, submitted).