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

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.