Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
J Nucl Med. 2020 Dec;61(12):1800-1805. doi: 10.2967/jnumed.120.243543. Epub 2020 May 15.
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.
肽受体放射性核素治疗（PRRT）使用放射性标记的奥曲肽是一种有效的治疗方法，用于表达生长抑素受体 2 的神经内分泌肿瘤。铜和铜的诊断和治疗潜力分别提供了使用单一生长抑素受体靶向肽结合物作为治疗诊断剂的可能性。一种 sarcophagine 笼胺配体，MeCOSar（5-（8-甲基-3,6,10,13,16,19-六氮杂双环[6.6.6]二十烷-1-基氨基）-5-氧戊酸），与（Tyr）-奥曲肽结合，称为 Cu-CuSarTATE，已被证明是一种成像剂，并在 10 名神经内分泌肿瘤患者中作为潜在的前瞻性剂量测定工具。本研究旨在探索 Cu-CuSarTATE 在神经内分泌肿瘤的临床前模型中的抗肿瘤疗效，并将其与标准 PRRT 药物 Lu-LuDOTA-Tyr-octreotate（Lu-LuTATE）进行比较。 比较了 AR42J（大鼠胰腺外分泌）肿瘤荷瘤小鼠中不同剂量的 Cu-CuSarTATE 与 Lu-LuTATE 的抗肿瘤疗效。 在单次给予 Cu-CuSarTATE（5 MBq）后 7 天，与载体对照组相比，肿瘤生长抑制率为 75%。给予 Lu-LuTATE（5 MBq）可抑制 89%的肿瘤生长。与对照组 12 天的存活时间相比，用 Cu-CuSarTATE 和 Lu-LuTATE 治疗后，存活时间延长至 21 天。在第二项研究中，评估了 PRRT 分次给药的疗效，比较了 30 MBq 的 Cu-CuSarTATE 或 Lu-LuTATE 作为单次静脉注射或 2 周后两次 15-MBq 分剂量的疗效。与单次给药相比，2 次给药显著提高了肿瘤的生存率（Cu-CuSarTATE：47 与 36 d [ = 0.036]；Lu-LuTATE：46 与 29 d [ = 0.040]）。 本研究表明，Cu-CuSarTATE 在 BALB/c 裸鼠中耐受性良好，对 AR42J 肿瘤具有高度疗效。在 2 周内分为 2 次给予 Cu-CuSarTATE 和 Lu-LuTATE 比单次给药更有效。Cu-CuSarTATE 在 AR42J 肿瘤模型中的抗肿瘤活性证明了这种新型药物在治疗表达生长抑素受体 2 的神经内分泌肿瘤中的临床评估的适用性。
