Abstract 3264: Preclinical multi-modal therapy of metastatic androgen independent prostate cancer using docetaxel, capecitabine, and a Lu-177-BB2r targeting peptide
Authors: Manuel Christopher A. , Rold Tammy L. , Sieckman Gary L. , Szczodroski Ashley F. , Hoffman Timothy J. 
Published: June 2012

Introduction: The Gastrin Releasing Peptide receptor (GRPr) also known as the bombesin receptor subtype 2 (BB2r) is currently of interest as a molecular target for the selective delivery of targeted radiation therapy for prostate cancer. We have previously demonstrated that 177Lu-177-DOTA-8-AOC-BBN(7-14)NH2, when administered concurrently with docetaxel, can achieve significant tumor control in flank xenograft models of androgen independent prostate cancer. We now present findings related to the use of 177Lu-177-DOTA-8-AOC-BBN(7-14)NH2 and chemotherapy for the treatment of systemic prostate cancer metastases using a SCID mouse model.

Methods: DOTA-8-AOC-BBN(7-14)NH2 was synthesized in house and radiolabeled with Lu-177. 177Lu-DOTA-8-AOC-BBN(7-14)NH2 was purified using analytical HPLC, which resulted in obtaining a high specific activity preparation. Systemic prostate metastases in SCID mice were created following intracardiac administration of 1×106 PC-3 cells. Micro-CT scans were performed weekly, beginning on day 24, to determine initial presence and extent of bone metastases. Treatment evaluation compared a chemotherapy only arm (docetaxel/capecitabine) with a multi-modal arm consisting of chemotherapy and targeted radiation therapy (TRT). Multi-modal therapy, consisting of docetaxel (8mg/kg; administered weekly), capecitabine (100mg/kg; administered daily (M-F) for 14 days followed by 7 day rest), and 177Lu-DOTA-8-AOC-BBN(7-14)NH2 (37MBq/25g; administered weekly), was delivered in two consecutive 3 week rounds. Animals were removed from the study based on evidence of morbidity as a result of either skeletal fracture and/or low body condition score.

Results: Survival analysis and Micro-CT evaluation at study endpoint (Day 84) revealed that 35% of the mice in the multi-modal therapy arm were responding to treatment (chemo + targeted Lu-177 radiation therapy) resulting in a mean survival of 57 +/- 5 d, whereas 100% of the chemotherapy only arm did not survive past Day 67, resulting in a Mean survival of 47 +/- 5d. Furthermore, Micro-CT analysis identified approximately 5 bony metastases per subject.

Conclusions: Our preclinical data suggests that 177Lu-DOTA-8-AOC-BBN(7-14)NH2 when used concurrently with docetaxel and capecitabine to control a model of androgen independent prostate cancer metastases can enhance overall mean survival times. Based on the survival limitations identified as a result of mortality causing SRE's, our findings further suggest that the use of bisphosphonates, to decrease the risk of bone fracture and delay the occurrence of bone metastases, may be the next logical addition to enhance multimodal therapy regimens combining 177Lu-DOTA-8-AOC-BBN(7-14)NH2 with chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2011-3264