{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:24:03Z","timestamp":1787833443597,"version":"build-2784847793"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Codec Chemical Co., Ltd., Tokyo, Japan"},{"name":"JSPS KAKENHI","award":["24H00540"],"award-info":[{"award-number":["24H00540"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>L-type amino acid transporter 1 (LAT1), which controls the neutral amino acid uptake across the cell membranes, has been frequently overexpressed in various human cancers. Overexpression of LAT1 is associated with higher proliferation and shorter patient survival in tumors. Here, upregulated LAT1 expression was observed in patient-derived canine bladder cancers (BCs), and a small-molecule LAT1 inhibitor (JPH203) successfully reduced BC tumor growth both in vitro and in vivo. Patient-derived cancer cells were collected from dogs with naturally occurring tumors at veterinary clinics in Japan, and the 2.5D cancer organoid culture system was generated following our previous studies. Compared with other canine cancers or normal bladder cells, the increased LAT1 expression was observed in 2 strains of BC organoids. JPH203 inhibited boronophenylalanine (BPA) uptake activity by more than 90% and suppressed cell proliferation dose-dependently. Deprivation of BPA uptake activity by JPH203 also regulated the phosphorylation of mTOR-related proteins. Furthermore, intraperitoneal administration of JPH203 decreased the growth and tumor weight of BC organoid-derived xenograft in immunodeficient mice with an induction of apoptosis and a decrease in LAT1 expression compared to vehicle-administered mice. Therefore, the present study demonstrates that JPH203 exerts anti-tumor effects in canine BC through modulation of the mTOR signaling pathway and supports further investigation of LAT1-targeted therapy for canine BC.<\/jats:p>","DOI":"10.3390\/ijms27177681","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:03:43Z","timestamp":1787832223000},"page":"7681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Tumor Potential of Selective L-Type Amino Acid Transporter (LAT1) Inhibitor, JPH203, in Patient-Derived Canine Bladder Cancer Organoids"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3095-4444","authenticated-orcid":false,"given":"Ting-Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minami","family":"Kawahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiya","family":"Goda","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Kanaya","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9368-1535","authenticated-orcid":false,"given":"Mohamed","family":"Elbadawy","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"},{"name":"Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Endou","sequence":"additional","affiliation":[{"name":"Codec Chemical Co., Ltd., 1-1-4, Kanda, Ogawa-Machi, Chiyoda-ku 101-0052, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichiro","family":"Ide","sequence":"additional","affiliation":[{"name":"Codec Chemical Co., Ltd., 1-1-4, Kanda, Ogawa-Machi, Chiyoda-ku 101-0052, 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Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"},{"name":"Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Uchide","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Usui","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hafliger, P., and Charles, R.P. (2019). The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102428"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.3390\/pr9071170","article-title":"Highly Specific L-Type Amino Acid Transporter 1 Inhibition by JPH203 as a Potential Pan-Cancer Treatment","volume":"9","author":"Achmad","year":"2021","journal-title":"Processes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1126\/science.122.3168.501","article-title":"Nutrition needs of mammalian cells in tissue culture","volume":"122","author":"Eagle","year":"1955","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1038\/s41598-022-06615-8","article-title":"Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer","volume":"12","author":"Kurozumi","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1349-7006.2011.02151.x","article-title":"Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis","volume":"103","author":"Furuya","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1440-1827.2008.02319.x","article-title":"L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer","volume":"59","author":"Sakata","year":"2009","journal-title":"Pathol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1038\/s41598-020-58136-x","article-title":"Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma","volume":"10","author":"Maimaiti","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.fct.2013.05.044","article-title":"L-Leucine and L-isoleucine enhance growth of BBN-induced urothelial tumors in the rat bladder by modulating expression of amino acid transporters and tumorigenesis-associated genes","volume":"59","author":"Xie","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Haining, Z., Kawai, N., Miyake, K., Okada, M., Okubo, S., Zhang, X., Fei, Z., and Tamiya, T. (2012). Relation of LAT1\/4F2hc expression with pathological grade, proliferation and angiogenesis in human gliomas. BMC Clin. Pathol., 12.","DOI":"10.1186\/1472-6890-12-4"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.bbrc.2013.08.020","article-title":"A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model","volume":"439","author":"Fukumoto","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1111\/cas.13021","article-title":"Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma","volume":"107","author":"Ohshima","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.prp.2015.03.007","article-title":"L-Type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling","volume":"211","author":"Ichinoe","year":"2015","journal-title":"Pathol. Res. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1349-7006.2009.01386.x","article-title":"L-type amino acid transporter 1 inhibitors inhibit tumor cell growth","volume":"101","author":"Oda","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_14","first-page":"217","article-title":"Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein","volume":"29","author":"Nakada","year":"2014","journal-title":"Histol. Histopathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jaci.2019.09.025","article-title":"Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation","volume":"145","author":"Cibrian","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1248\/bpb.31.1096","article-title":"BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells","volume":"31","author":"Kim","year":"2008","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","unstructured":"Endou, H., Kanai, Y., Tsujihara, K., and Saito, K. (2008). Aromatic Amino Acid Derivatives and Medicinal Compositions. (7,345,068 B2), U.S. Patent."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1200\/JCO.2018.36.15_suppl.2519","article-title":"First-in-human phase I study of JPH203, L-type amino acids transporter 1 inhibitor, in patients with advanced solid tumors","volume":"36","author":"Okano","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1292\/jvms.12-0356","article-title":"L-type amino acid transporter 1 (LAT1) expression in canine mammary gland tumors","volume":"75","author":"Fukumoto","year":"2013","journal-title":"J. Vet. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1292\/jvms.14-0392","article-title":"Analysis of L-type amino acid transporter in canine hepatocellular carcinoma","volume":"77","author":"Ogihara","year":"2015","journal-title":"J. Vet. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113597","DOI":"10.1016\/j.biopha.2022.113597","article-title":"Establishment of a direct 2.5D organoid culture model using companion animal cancer tissues","volume":"154","author":"Abugomaa","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","first-page":"47","article-title":"Naturally-occurring canine transitional cell carcinoma of the urinary bladder A relevant model of human invasive bladder cancer","volume":"5","author":"Knapp","year":"2000","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_23","first-page":"97","article-title":"Association Between XRCC3 Thr241Met Gene Polymorphism and Susceptibility to Urothelial Carcinoma of the Bladder","volume":"40","author":"Ahmed","year":"2022","journal-title":"Benha. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"255","DOI":"10.21608\/bjas.2021.169460","article-title":"Evaluation of IGF-2 Gene Expression in Urine and its Potential Use as Biomarker for Bladder Cancer","volume":"6","author":"Sherif","year":"2021","journal-title":"Benha J. Appl. Sci."},{"key":"ref_25","first-page":"1281","article-title":"L-type amino acid transport and cancer: Targeting the mTORC1 pathway to inhibit neoplasia","volume":"5","author":"Wang","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.cmet.2013.10.001","article-title":"mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation","volume":"18","author":"Morita","year":"2013","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.1111\/jcmm.17553","article-title":"Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells","volume":"26","author":"Nishikubo","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"599","DOI":"10.4196\/kjpp.2017.21.6.599","article-title":"JPH203, a selective L-type amino acid transporter 1 inhibitor, induces mitochondria-dependent apoptosis in Saos2 human osteosarcoma cells","volume":"21","author":"Choi","year":"2017","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00726-025-03456-3","article-title":"Targeting LAT1 with JPH203 to reduce TNBC proliferation and reshape suppressive immune microenvironment by blocking essential amino acid uptake","volume":"57","author":"Zhao","year":"2025","journal-title":"Amino Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3892\/ol.2023.13757","article-title":"LAT1 is associated with poor prognosis and radioresistance in head and neck squamous cell carcinoma","volume":"25","author":"Kawasaki","year":"2023","journal-title":"Oncol. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1111\/cas.16191","article-title":"The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism","volume":"115","author":"Saito","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ogawa, M., Tanaka, A., Maekawa, M., Namba, K., Otani, Y., Shia, J., Wang, J.Y., and Roehrl, M.H. (2024). Protein expression of the amino acid transporter SLC7A5 in tumor tissue is prognostic in early-stage colorectal cancer. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0298362"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1007\/s10637-020-00924-3","article-title":"First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors","volume":"38","author":"Okano","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1111\/cas.14118","article-title":"Establishment of a novel experimental model for muscle-invasive bladder cancer using a dog bladder cancer organoid culture","volume":"110","author":"Elbadawy","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s13046-018-0907-z","article-title":"The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model","volume":"37","author":"Graff","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"119823","DOI":"10.1016\/j.biomaterials.2020.119823","article-title":"Efficacy of primary liver organoid culture from different stages of non-alcoholic steatohepatitis (NASH) mouse model","volume":"237","author":"Elbadawy","year":"2020","journal-title":"Biomaterials"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7681\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:04:05Z","timestamp":1787832245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177681"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177681","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}