1193. Radiation Sensitisation and Dose-Modified Vascular Targeting Causes Selective Thrombosis and Complete Occlusion in Arteriovenous Malformations
Authors: Andrew Gauden; Vivienne Lee; Sinduja Subramanian; Vaughan Moutrie; Zhenjun Zhao; Lucinda McRobb; Marcus Stoodley (Brunswick, Australia)
Despite current treatments, ⅓ of brain arteriovenous malformations (AVMs) are untreatable. Our goal is to develop a novel vascular targeting approach for these patients using radiosurgery as a priming tool for selective target expression. Preliminary studies demonstrated proof-of-principle that vascular targeting causing occlusion in an AVM animal model could be achieved using a single high dose (300 ug/kg) of phosphatidylserine-targeting Annexin V/Thrombin prothrombotic conjugate. However, no difference in occlusion rates were noted with sensitising gamma knife radiosurgery (GKS). We hypothesise that dose modification of the targeting agent can improve the selectivity of AVM targeting with prior GKS.
A validated rat AVM animal model was used by surgical anastomosing the external jugular vein to the common carotid artery. The model AVM was then treated with GKS (20 Gy). Annexin V/Thrombin conjugate was administered intravenously as a single dose (150 ug/kg) 21 days post-GKS or sham, or as two equivalent doses at 21 and 24 days (n=8 per group). AVM patency was assessed 4 weeks following conjugate administration by angiogram and histologically.
Using a single conjugate dose, 80% of GKS-treated animals had evidence of AVM occlusion compared to 13% of sham-GKS animals (p=0.03). This difference was more pronounced with the double conjugate dose; 78% of animals in the GKS-treated animals demonstrating AVM occlusion compared to 0% in the sham-GKS group (p=0.003). Histological evidence of AVM thrombus was found in sham and GKS groups of both single and double dose animals.
This study demonstrates effective dose modification of our Annexin V/Thrombin conjugate and thrombosis and occlusion of AVMs both radiologically and histologically. Modification of conjugate dose and delivery allows for increased selective targeting of endothelium pretreated with GKS and may have clinical application in the treatment of human AVMs.