Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 211166, China.
Cell Rep Med. 2023 Apr 18;4(4):100960. doi: 10.1016/j.xcrm.2023.100960. Epub 2023 Mar 31.
Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1 human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, At-AITM. A single dose of At-AITM (2.96 MBq) in mGluR1 cancers exhibits long-lasting in vivo antitumor efficacy across seven subtypes of four of the most common tumors, namely, breast cancer, pancreatic cancer, melanoma, and colon cancers, with little toxicity. Moreover, complete regression of mGluR1 breast cancer and pancreatic cancer is observed in approximate 50% of tumor-bearing mice. Mechanistically, the functions of At-AITM are uncovered in downregulating mGluR1 oncoprotein and inducing senescence of tumor cells with a reprogrammed senescence-associated secretory phenotype. Our findings suggest α-radiopharmaceutical therapy with At-AITM can be a useful strategy for mGluR1 pan-cancers, regardless of their tissue of origin.
代谢型谷氨酸受体 1（mGluR1）是谷氨酸能信号的关键介质，在肿瘤细胞中常过度表达，是大多数癌症有吸引力的药物靶点。在这里，我们提出了一种靶向放射性药物治疗策略，该策略通过利用小分子α（α）发射放射性药物 At-AITM，拮抗识别 mGluR1 并根除 mGluR1 人类肿瘤。在七种最常见的四种肿瘤（乳腺癌、胰腺癌、黑色素瘤和结肠癌）的 mGluR1 癌症中，单次给予 At-AITM（2.96 MBq）可表现出持久的体内抗肿瘤疗效，毒性很小。此外，在大约 50%的荷瘤小鼠中观察到 mGluR1 乳腺癌和胰腺癌的完全消退。从机制上讲，At-AITM 的作用是下调 mGluR1 癌蛋白并诱导肿瘤细胞衰老，具有重新编程的衰老相关分泌表型。我们的研究结果表明，At-AITM 的α-放射性药物治疗可能是 mGluR1 泛癌的一种有用策略，而与肿瘤的起源组织无关。
