Life science
Medical & healthcare, Drug development, Accelerator technology

Establishment of nuclear medicine targeting LAT1,cancer type amino acid transporter
MS-CORE, FRC, Graduate School of Science
Professor Kazuko Kaneda-Nakashima
https://researchmap.jp/read0131912?lang=en

Life science

Abstract
Our research group is a cross-disciplinary research group. We
have a one-stop system from manufacturing nuclides to non-clinical trials, and we also work with affiliated hospitals that can conduct clinical trials. First, we produced astatine*1-211(211At), a shortlived alpha-emitting nuclide, using an accelerator. Second, after
separating 211At, we established 211At labeled α-methyl-L-tyrosine,
which an amino acid, as a novel targeted radioisotope therapy,
which an amino acid, with 211At, an α-emitter, named 211At-AAMT.
211
At-AAMT was effectively uptake into cancer cells by the aminoacid transporter LAT1*2. α-emitter combines high linear energy
transfer with minimal tissue penetration, thus damaging cancer
cells lethally while sparing surrounding normal tissue. This strategy
may prove a breakthrough in the management of intractable or advanced cancers.

astatic disease. Since LAT1 is expressed in many types of cancer,
At-AAMT may be applicable to various cancer types. It has thepotential to become, so to speak, a “universal remedy”.
211▍ Background & Results
It is well known that a cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in several kinds of human cancer tissues. Inhibiting the function of LAT1 has been known to induce anti-cancer effects, such as growth inhibition and cell death.
However, there had been limited progress in the development ofagents targeted radioisotope therapy to LAT1 so far. Our multidisciplinary research team at Institute for radiation sciences in Osaka
University has established a targeted α-therapy with a novel drug
targeting LAT1.
We selected astatine-211(211At) as labeled nuclides, it is because we have advanced technology about astatine-211 in Japan.
Targeted α-therapy selectively delivers α-emitters to cancers;
the advantage over conventional β-therapy is that alpha decay ishighly targeted, and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The shorthalf-life and limited tissue penetration of alpha emitting nuclide ensures high therapeutic effects with few side-effects to surrounding
normal cells.
Next, to deliver the astatine-211 into cancer cells, we labeled it
to α-Methyl-L-tyrosine, which has high affinity for LAT1. 211At-AAMT
was uptake rapidly into the cancer cells as nutrition and injured
these cells. 211At-AAMT inhibited tumor growth in a PANC1 pancreatic cancer model (Fig.1). In addition, metastasis suppression wasobserved in a lung metastasis model of B16F10 melanoma (Fig.2).

Fig. 1: The efficacy of 211At-AAMT using the PANC-1 xenograft model. Tumor
growth inhibition by 211At-AAMT (Left). Coronal images of 211At-AAMT in tumor-bearing model (right).

Fig.2: Tumor metastasis inhibition via 211At-AAMT using a B16F10 model.
Photos of experimental mice lung.

▍ Significance of the research and Future perspective
Adding to efficacy is dosing convenience. As an injectable
short-range nuclear medicine, 211At-AAMT may be administered in
outpatient clinics, a huge advantage over conventional radiation
protocols, and may even be an alternative to surgery in specificcancers. This approach has immense potential to revolutionize
radionuclide therapy of not only pancreatic cancer but other malignancies that lack effective treatment including advanced or met-

*1 Astatine: Atomic number 85, and group 17 (halogen). Chemical element withthe symbol At. All of astatine’s isotopes are short-lived. Naming after Greek
astatos, meaning “unstable”.
*2 LAT1: L-type amino acid transporter 1. LAT1 is a heterodimeric membranetransport protein that preferentially transports branched-chain (valine, leucine,isoleucine) and aromatic (tryptophan, tyrosine, phenylalanine) amino acids.

P a t e n t Japanese Patent Application No. 2018-048562, PCT/JP2019/030006, Japanese Patent Application No. 2022-150608
Kaneda-Nakashima, Kazuko; Zhang, Zijian; Manabe, Yoshiyuki et al. α-Emitting cancer therapy using 211At-AAMT targeting LAT1. Cancer Sci. 2021,
Tr e a t i s e112(3), 1132-1140, doi: 10.1111/cas.14761
URL https://www.frc.sci.osaka-u.ac.jp/project/ms_core
K e y w o r d nuclear medicine, alpha emitter, astatine-211, amino-acid, transporter