Peptide Receptor Radionuclide Therapy with <sup>67</sup>Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model
Carleen Cullinane, Charmaine M. Jeffery, Peter Roselt, Ellen M. van Dam, Susan Jackson, K. Kuan, Price Jackson, David Binns, Jessica Van Zuylekom, Matthew Harris, Rodney J. Hicks, Paul S. Donnelly
Abstract
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 <sup>64</sup>Cu and <sup>67</sup>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<sup>3</sup>)-octreotate, called <sup>64</sup>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 <sup>67</sup>Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, <sup>177</sup>Lu-LuDOTA-Tyr<sup>3</sup>-octreotate (<sup>177</sup>Lu-LuTATE). <b>Methods:</b> The antitumor efficacy of various doses of <sup>67</sup>Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor–bearing mice was compared with <sup>177</sup>Lu-LuTATE. <b>Results:</b> Seven days after a single administration of <sup>67</sup>Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of <sup>177</sup>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 <sup>67</sup>Cu-CuSarTATE and <sup>177</sup>Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of <sup>67</sup>Cu-CuSarTATE or <sup>177</sup>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 (<sup>67</sup>Cu-CuSarTATE: 47 vs. 36 d [<i>P</i> = 0.036]; <sup>177</sup>Lu-LuTATE: 46 vs. 29 d [<i>P</i> = 0.040]). <b>Conclusion:</b> This study demonstrates that <sup>67</sup>Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of <sup>67</sup>Cu-CuSarTATE and <sup>177</sup>Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of <sup>67</sup>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.