Summary
This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12–85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25–40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.
Similar content being viewed by others
References
Ganapathy V, Thangaraju M, Prasad PD (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther 121:29–40
Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, Vander Heiden MG (2016) Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell 36:540–549
Christensen HN (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:43–77
Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273:23629–23632
Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y (1999) Identification and functional characterization of a Na+−independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751
Babu E, Kanai Y, Chairoungdua A, Kim DK, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H (2003) Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 278:43838–43845
Bodoy S, Martin L, Zorzano A, Palacín M, Estévez R, Bertran J (2005) Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem 280:12002–12011
Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H (2001) Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514:291–302
Liu XM, Reyna SV, Ensenat D, Peyton KJ, Wang H, Schafer AI, Durante W (2004) Platelet-derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: role in cell growth. FASEB J 18:768–770
Kim CS, Moon IS, Park JH, Shin WC, Chun HS, Lee SY, Kook JK, Kim HJ, Park JC, Endou H, Kanai Y, Lee BK, Kim DK (2010) Inhibition of L-type amino acid transporter modulates the expression of cell cycle regulatory factors in KB oral cancer cells. Biol Pharm Bull 33:1117–1121
Yothaisong S, Dokduang H, Anzai N, Hayashi K, Namwat N, Yongvanit P, Sangkhamanon S, Jutabha P, Endou H, Loilome W (2017) Inhibition of L-type amino acid transporter 1 activity as a new therapeutic target for cholangiocarcinoma treatment. Tumor Biol 39:1010428317694545
Kobayashi H, Ishii Y, Takayama T (2005) Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J Surg Oncol 90:233–238
Nakanishi K, Ogata S, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H, Kawai T (2007) Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Arch 451:681–690
Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T, Kanai Y, Endou H, Nakajima T, Mori M (2008) Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer 98:742–748
Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H, Okayasu I (2009) L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int 59:7–18
Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, Anzai N, Suzuki Y, Endou H, Okayasu I (2011) High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions. Pathol Int 61:281–289
Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T (2012) Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci 103:382–389
Kaira K, Sunose Y, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Segawa A, Furuya M, Mori M, Oyama T, Takeyoshi I (2012) Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer. Br J Cancer 107:632–638
Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, Takayasu Y, Takahashi K, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Oyama T, Chikamatsu K (2014) Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. Br J Cancer 110:2506–2513
Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I (2013) Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer. BMC Cancer 13:482
Yanagisawa N, Hana K, Nakada N, Ichinoe M, Koizumi W, Endou H, Okayasu I, Murakumo Y (2014) High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas. Cancer Med 3:1246–1255
Oda K, Hosoda N, Endo H, Saito K, Tsujihara K, Yamamura M, Sakata T, Anzai N, Wempe MF, Kanai Y, Endou H (2010) L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci 101:173–179
Wempe MF, Rice PJ, Lightner JW, Jutabha P, Hayashi M, Anzai N, Wakui S, Kusuhara H, Sugiyama Y, Endou H (2012) Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound. Drug Metab Pharmacokinet 27:155–161
Toyoshima J, Kusuhara H, Wempe MF, Endou H, Sugiyama Y (2013) Investigation of the role of transporters on the hepatic elimination of an LAT1 selective inhibitor JPH203. J Pharm Sci 102:3228–3238
Hein DW, Doll MA (2012) Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics 13:31–41
Häfliger TP, Charles RP (2019) The L-type amino acid transporter LAT1—an emerging target in Cancer. Int J Mol Sci 20:2428
Wang Q, Holst J (2015) L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res 5:1281–1294
Salisbury TB, Arthur S (2018) The regulation and function of the L-type amino acid transporter 1 (LAT1) in Cancer. Int J Mol Sci 19:2373
Singh N, Ecker GF (2018) Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, LAT1. Int J Mol Sci 19:1278
Nakada N, Mikami T, Hana K, Ichinoe M, Yanagisawa N, Yoshida T, Endou H, Okayasu I (2014) Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein. Histol Histopathol 29:217–227
Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutte E, Massard PA, de la Ballina LR, Endou H, Wempe M, Palacin M, Parks SK, Pouyssegur J (2016) Genetic disruption of the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res 76:4481–4492
Rosilio C, Nebout M, Imbert V, Griessinger E, Neffati Z, Benadiba J, Hagenbeek T, Spits H, Reverso J, Ambrosetti D, Michiels JF, Bailly-Maitre B, Endou H, Wempe MF, Peyron JF (2015) L-type amino acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of t-cell lymphoblastic lymphoma/t-cell acute lymphoblastic leukemia. Leukemia 29:1253–1266
Kaira K, Oriuchi N, Shimizu K, Ishikita T, Higuchi T, Imai H, Yanagitani N, Sunaga N, Hisada T, Ishizuka T, Kanai Y, Endou H, Nakajima T, Endo K, Mori M (2009) Evaluation of thoracic tumors with (18)F-FMT and (18)F-FDG PET-CT: a clinicopathological study. Int J Cancer 124:1152–1160
Wempe MF, Jutabha P, Kumar V, Fisher JA, Waers K, Holt MD, Dodson AM, Bautista J, Gehr DT, Backos DS, Kumar A, Rice PJ, Anzai N, Saito K, Oda K, Kanai Y, Endou H (2019) Developing selective L-Amino Acid Transport 1 (LAT1) inhibitors: A Structure-Activity Relationship overview. Med Res Arch. https://doi.org/10.18103/mra.v7i12.2014
Janpipatkul K, Suksen K, Borwornpinyo S, Jearawiriyapaisarn N, Hongeng S, Piyachaturawat P, Chairoungdua A (2014) Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration. Cell Signal 26:1668–1679
Yothaisong S, Namwat N, Yongvanit P, Khuntikeo N, Puapairoj A, Jutabha P, Anzai N, Tassaneeyakul W, Tangsucharit P, Loilome W (2017) Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance. Parasitol Int 66:471–478
Sabbagh A, Darlun P, Crouau-Roy B, Poloni ES (2011) Arylamine N-acetyltransferase (NAT2) genetic diversity and traditional subsistence: a worldwide population survey. PLoS One 6:e18507
Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Waters JS, Hobbs C, Barber S, Ryder D, Ramage JK, Davies LM, Bridgewater JA, Valle JW (2019) ABC-06 | a randomised phase III, multi-Centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol 37:4003 (abstract)
Ueno M, Ikeda M, Morizane C, Kobayashi S, Ohno I, Kondo S, Okano N, Kimura K, Asada S, Namba Y, Okusaka T, Furuse J (2019) Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol 4:611–621
Acknowledgments
The authors thank Masuhiro Yoshitake and Yoshinori Bamba for their support in the NAT2 analysis.
Funding
This study was sponsored by J-Pharma Co., Ltd.
Author information
Authors and Affiliations
Contributions
Conception and design, N.O., H.E., and J.F.; Administrative support, H.E.; Provision of study materials or patients, N.O., D.N., K.K., T.K., F.N., and J.F.; Collection and assembly of data, N.O., D.N., K.K., T.K., F.N., and J.F.; Data analysis and interpretation, N.O., D.N., F.N., H.E., and J.F.; Manuscript writing, All authors.; Final approval of manuscript, All authors.
Corresponding author
Ethics declarations
Conflict of interest
Okano N. received personal fees from Merck Serono, Taiho, Eisai and J-Pharma. Naruge D. declares that he has no conflict of interest. Kawai K. declares that he has no conflict of interest. Kobayashi T. declares that he has no conflict of interest. Nagashima F. received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Merck Serono, Takeda, Kyowa Hakko Kirin, Sanofi Mochida, Janssen and Nestle. Endou H. received salary from J-Pharma, and has pending patents for LAT1, JPH203 and application of JPH203 in Phase I study of solid tumors. Furuse J. received grants from J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai, NanoCarrier, Mochida, Baxalta and Sanofi, and received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly Japan, Astellas, Ono, Pfizer, Bayer, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi, J-Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofi, Sandoz, Otsuka, Zeria, Fujifilm, Astra Zeneca, Asahi Kasei, Shire, Mochida, Nippon Kayaku, EA pharma, Sawai and Teijin Pharma.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board and with the 1964 Helsinki declaration and its later amendments. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Okano, N., Naruge, D., Kawai, K. et al. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs 38, 1495–1506 (2020). https://doi.org/10.1007/s10637-020-00924-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-020-00924-3