211At-AITM RPT: a tumor agnostic therapeutic strategy for mGluR1–positive human cancers

Introduction: Since glutaminolysis's observation that most cancers exhibit increased glutamine metabolism (1), metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, has been intensively pursued as an attractive drug target (2). Here, we present a tumor agnostic radiopharmaceutical therapy (RPT) strategy that antagonistically recognizes mGluR1 and eradicates mGluR1⁺ human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, ²¹¹At-AITM(Fig. 1A).

Methods: The α-radiopharmaceutical ²¹¹At-AITM was synthesized by reacting a stannyl precursor with ²¹¹At in the presence of an oxidizing agent (3). The therapeutic efficacy and safety profile of ²¹¹At-AITM RPT were evaluated in xenograft mice bearing 7 subtypes of cells characteristic to 4 types of solid tumors－both those with and without mGluR1 expression. The phenotypic variations of tumor cells following ²¹¹At-AITM exposure were investigated by immunohistochemistry and qRT-PCR.

Results: A single dose of ²¹¹At-AITM (2.96 MBq) in mGluR1⁺ cancers exhibited unequivocal and durable antitumor efficacy across 7 subtypes of 4 of the most common solid tumors comprising breast cancer, pancreatic cancer, melanoma, and colon cancer, with little toxicity, while showing minimal effects against mGluR1^- cancers (Fig. 1B-C). Remarkably, complete regression of mGluR1⁺ breast cancer and pancreatic cancer was observed in approximate 50% of tumor-bearing mice. Mechanistic studies revealed novel roles of a-RPT in downregulating the oncoprotein expression to mitigate the proliferative potential of cancer cells and induce the senescence of cancer cells with a reprogrammed senescence-associated secretory phenotype.

Conclusions: ²¹¹At-AITM RPT is an innovative strategy for mGluR1⁺ pan-cancers, regardless of their tissue of origin. The dual functions of ²¹¹At-AITM that downregulate mGluR1 expression and induce tumor-antagonizing senescence imply an unreported and sophisticated mechanism through which a-RPT governs cancer cell fate. Our findings could be valuable in the development of unprecedented precision RPT strategies for cancer intervention targeting glutamine/glutamate metabolism.

References

1.DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., et al. Cell Metab. 2008; 7:11-20.

2.Pollock PM, Cohen-Solal, K., Sood, R., et al. Nat Genet. 2003; 34:108-112.

3.Xie L, Hanyu, M., Fujinaga, M., et al. J Nucl Med.2020; 61:242-248.

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