Peptide Receptor Radionuclide Therapy with Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of Cu and Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr)-octreotate, called Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, Lu-LuDOTA-Tyr-octreotate (Lu-LuTATE). The antitumor efficacy of various doses of Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with Lu-LuTATE. Seven days after a single administration of Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both Cu-CuSarTATE and Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of Cu-CuSarTATE or Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (Cu-CuSarTATE: 47 vs. 36 d [ = 0.036]; Lu-LuTATE: 46 vs. 29 d [ = 0.040]). This study demonstrates that Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of Cu-CuSarTATE and Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.