PT  - JOURNAL ARTICLE
AU  - Xie, Lin
AU  - Hanyu, Masayuki
AU  - Zhang, Yiding
AU  - Zhang, Lulu
AU  - Fujinaga, Masayuki
AU  - Minegishi, Katsuyuki
AU  - Ohkubo, Takayuki
AU  - Nagatsu, Kotaro
AU  - Zhang, Ming-Rong
TI  - <strong>211At-AITM RPT: a tumor agnostic therapeutic strategy for mGluR1–positive human cancers</strong>
DP  - 2023 Jun 01
TA  - Journal of Nuclear Medicine
PG  - P761--P761
VI  - 64
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/64/supplement_1/P761.short
4100  - http://jnm.snmjournals.org/content/64/supplement_1/P761.full
SO  - J Nucl Med2023 Jun 01; 64
AB  - P761 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.References1.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.