2. Academic Validation
  3. A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy

A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy

  • Cell Rep Med. 2023 Mar 3;100960. doi: 10.1016/j.xcrm.2023.100960.
Lin Xie 1,  Lulu Zhang 2,  Kuan Hu 3,  Masayuki Hanyu 4,  Yiding Zhang 4,  Masayuki Fujinaga 4,  Katsuyuki Minegishi 4,  Takayuki Ohkubo 4,  Kotaro Nagatsu 4,  Cuiping Jiang 2,  Takashi Shimokawa 5,  Kazuma Ashisuke 5,  Noriyuki Okonogi 5,  Shigeru Yamada 5,  Feng Wang 6,  Rui Wang 7,  Ming-Rong Zhang 8
Affiliations

Affiliations

  • 1 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan. Electronic address: [email protected].
  • 2 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.
  • 3 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 4 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 5 Department of Charged Particle Therapy Research, Quantum Life and Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 6 Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 8 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan. Electronic address: [email protected].
PMID: 37003259 DOI: 10.1016/j.xcrm.2023.100960
Abstract

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, 211At-AITM. A single dose of 211At-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 211At-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 211At-AITM can be a useful strategy for mGluR1+ pan-cancers, regardless of their tissue of origin.

Keywords

(211)At-AITM; alpha-emitting radiopharmaceutical; glutamine metabolism; metabotropic glutamate receptor 1; oncoprotein; pan-cancer; reprogrammed senescence-associated secretory phenotype; senescence; targeted alpha radiopharmaceutical therapy; α−particle.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101845
    99.85%, mGluR Inhibitor