In vivo biodistribution and efficacy evaluation of NeoBOMB1, a theranostic agent targeting GRPR, in mice bearing GastroIntestinal Stromal Tumor

Objectives: The gastrin-releasing peptide receptor (GRPR), also known as bombesin receptor subtype 2, is a G-protein-coupled receptor expressed in various cancers. Multiple radiolabeled GRPR ligands have been evaluated. Among them, NeoBOMB1 has been shown to exhibit excellent tumor uptake and favorable pharmacokinetics for imaging in mice bearing prostate tumors, and its translational prospects were further supported by the successful visualization of prostate cancer lesions in men using 68Ga-NeoBOMB1 and PET/CT1. The aim of the present study was to evaluate the biodistribution and efficacy of this new theragnostic agent in the setting of Gastrointestinal Stromal Tumors (GIST). The study was conducted within the MITIGATE project (European Community FP7, #602306). Methods. A total of 76 six week old male SCID mice bearing subcutaneous GIST-882 tumors were employed. For the biodistribution substudy (5-6 mice per group), 177Lu-NeoBOMB1 was injected intravenously (200 pmol/0.8 MBq) and the biodistribution was evaluated by organ sampling and gamma-well counting at several time points (1h, 4h, 24h, 48h, 96h, and 168h). Moreover, the specificity was evaluated at 4h by co-injecting an excess of 40 nmol unlabeled NeoBOMB1. Results were expressed as a percentage injected dose per gram (%ID/g). For the efficacy substudy, control mice were injected with saline (Control group, n=13), whereas treated mice received either 400 pM (400 pM group, n=14) or 800 pM (800 pM group, n=13) of 37 MBq (i.v.) of 177Lu-NeoBOMB1 once a week for 3 weeks. SPECT/CT imaging was performed at 24h on a subgroup of mice, and tumor volume was determined up to 100 days following 177Lu-NeoBOMB1 injection. Results: Biodistribution- At 4h post-injection (pi), elevated 177Lu-NeoBOMB1 uptake was found in the GIST tumor (19.1 ± 3.9 %ID/g) and the pancreas (8.5 ± 2.0 %ID/g), which was significantly reduced to 0.3 ± 0.1 %ID/g and 0.1 ± 0.0 %ID/g, respectively, by in vivo competition. From 24h to 168h pi, 177Lu-NeoBOMB1 uptake was lower than 2 %ID/g in all investigated tissues with the exception of the GIST tumor. Indeed, tumor uptake was of 13.4 ± 3.5, 10.5 ± 1.6, 5.9 ± 0.3 and 2.5 ± 0.7%ID/g at 24h, 48h, 96h and 168h, resulting in elevated (>10) tumor-to-kidney, tumor-to-liver and tumor-to-pancreas ratios. Efficacy- GIST-882 tumors were readily observable at 24h by SPECT/CT imaging. Interestingly, 177Lu-NeoBOMB1 tumor uptake in 400 pM group mice was found to be significantly higher than that observed i