VCAM-1 Targeted Alpha-Particle Therapy for Early Brain Metastases.
Corroyer-Dulmont A., Valable S., Falzone N., Frelin-Labalme A-M., Tietz O., Toutain J., Sarmiento Soto M., Divoux D., Chazaviel L., Pérès EA., Sibson NR., Vallis KA., Bernaudin M.
BACKGROUND: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumour cells have invaded the brain. Vascular cell adhesion molecule-1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining 212Pb with an anti-VCAM-1 antibody (212Pb-αVCAM-1). METHODS: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. 21 days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared to that observed after standard EBRT. RESULTS: 212Pb-αVCAM-1 was taken up into early BM with a tumour/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108 disintegrations per g of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared to EBRT (p<0.001), translating to an increase in overall survival of 29% at 40 days post-RX (p<0.01). No major toxicity was observed. CONCLUSIONS: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumour growth inhibition.