Abstract 5744: Preclincial therapy of androgen independent prostate cancer using combinationLu-177-BB2r targeting peptides and docetaxel

Introduction: The bombesin receptor subtype 2 (BB2r) is an attractive target for the selective delivery of peptide receptor targeted radiation therapy for androgen independent prostate cancer (AIPC). Earlier work from our group has focused on the use of the BB2r agonist 177Lu-177-DOTA-8-AOC-BBN(7-14)NH2 administered concurrently with docetaxel to achieve tumor control in flank xenograft models of AIPC. We now present a direct comparison of 177Lu-BB2r agonist verses 177Lu-BB2r antagonist demonstrating the superiority of employing the BB2r antagonist, RM2, for the treatment of AIPC using a SCID mouse model. Methods: DOTA-8-AOC-BBN(7-14)NH2 was synthesized in house. RM2 was commercially synthesized. 177Lu radiolabeled peptides were prepared and purified using analytical HPLC resulting in a high specific activity preparation. The AIPC tumor bearing mice were created following bilateral flank inoculation of 1X106 PC-3 cells. Pharmacokinetic analysis and Micro-SPECT imaging of 177Lu-RM2 was conducted out to 14 days post administration. Survival study design compared a 177Lu-BB2r agonist /docetaxel arm with a 177Lu-BB2r antagonist /docetaxel arm including a non-treated tumor bearing control arm. Multi-modal therapy consisting of docetaxel (8mg/kg; administered weekly) and 177Lu-BB2r peptide therapy (37MBq/25g; administered weekly) was delivered for six consecutive weeks. Subjects were removed from study based on evidence of morbidity and body condition score. Results: Pharmacokinetic analysis and Micro-SPECT imaging of 177Lu-RM2 demonstrated prolonged tumor retention with minimal non-target tissue accumulation observed within 24 hours post administration. Survival analysis at Day 100 demonstrated that 67% of the mice in the multi-modal BB2r antagonist therapy arm (chemo + targeted 177Lu radiation therapy) were responding to treatment as compared to a 17% survival of the combination BB2r agonist/chemotherapy arm only arm at the same time point. 177Lu-RM2 antagonist therapy demonstrated tumor regression and complete control whereas 177Lu agonist therapy tumor regression was short lived with complete regrowth observed 45 days following last treatment. Conclusions: Our preclinical data suggests that 177Lu-BB2r antagonist therapy is superior to 177Lu-BB2r agonist therapy when used concurrently with docetaxel employing a preclinical model of AIPC. The use of 177Lu-BB2r antagonists permits accurate SPECT imaging of therapeutic agent localization at prolonged times post