Peptide Receptor Radionuclide Therapy with ⁶⁷Cu-CuSarTATE is Highly Efficacious Against a Somatostatin Positive Neuroendocrine Tumor Model

Abstract

Peptide receptor radionuclide therapy using radiolabeled octreotate is an effective treatment for somatostatin receptor 2 expressing neuroendocrine tumors. The diagnostic and therapeutic potential of copper-64 and copper-67, respectively, offers the possibility of using a single somatostatin receptor targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar, conjugated to (Tyr3)-octreotate called, ⁶⁴Cu-CuSarTATE, was demonstrated as an imaging agent and potential prospective dosimetry tool in ten patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of ⁶⁷Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard peptide receptor radionuclide therapy agent, ¹⁷⁷Lu-LuDOTA-Tyr3-octreotate (¹⁷⁷Lu-LuTATE). METHODS: The antitumor efficacy of various doses of ⁶⁷Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor bearing mice was compared with ¹⁷⁷Lu-LuTATE. RESULTS: Seven days after a single administration of ⁶⁷Cu-CuSarTATE (5 MBq) tumor growth was inhibited by 75% compared to vehicle control. Administration of ¹⁷⁷Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival, was extended from 12 days in the control group to 21 days following following treatment with both ⁶⁷Cu-CuSarTATE and ¹⁷⁷Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq ⁶⁷Cu-CuSarTATE or ¹⁷⁷Lu-LuTATE, either as a single intravenous injection or as two 15 MBq fractions two weeks apart. Treatment of tumors with two fractions significantly improved survival when compared to delivery as a single fraction (⁶⁷Cu-CuSarTATE: 47 vs 36 days; P = 0.036; ¹⁷⁷Lu-LuTATE: 46 vs 29 days; P = 0.040). CONCLUSION: This study demonstrates that ⁶⁷Cu-CuSarTATE is well tolerated in Balb/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of ⁶⁷Cu-CuSarTATE and ¹⁷⁷Lu-LuTATE divided into two fractions over two weeks was more efficacious than that of a single fraction. The antitumor activity of ⁶⁷Cu-CuSarTATE in the AR42J tumor model demonstrating the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2 expressing neuroendocrine tumors.