First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors

Okano, Naohiro; Nagashima, Daisuke; Kawai, Kirio; Kobayashi, Takaaki; Nagashima, Fumio; Endou, Hitoshi; Furuse, Junji

doi:10.1007/s10637-020-00924-3

Cited by 99 publications

(114 citation statements)

References 37 publications

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“…So far, only one compound which targets LAT1 reached the clinical trial for cancer treatment, i.e. the tyrosine analogue JPH203 16,17 . In the context of drug development, parallel to inhibitors, also prodrugs are designed given the ability of LAT1 to transport also thyroid hormones, L-DOPA and gabapentin, i.e.…”

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confidence: 99%

ATP modulates SLC7A5 (LAT1) synergistically with cholesterol

Cosco

Scalise

Colas

et al. 2020

Sci Rep

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The plasma membrane transporter hLAT1 is responsible for providing cells with essential amino acids. hLAT1 is over-expressed in virtually all human cancers making the protein a hot-spot in the fields of cancer and pharmacology research. However, regulatory aspects of hLAT1 biology are still poorly understood. A remarkable stimulation of transport activity was observed in the presence of physiological levels of cholesterol together with a selective increase of the affinity for the substrate on the internal site, suggesting a stabilization of the inward open conformation of hLAT1. A synergistic effect by ATP was also observed only in the presence of cholesterol. The same phenomenon was detected with the native protein. Altogether, the biochemical assays suggested that cholesterol and ATP binding sites are close to each other. The computational analysis identified two neighboring regions, one hydrophobic and one hydrophilic, to which cholesterol and ATP were docked, respectively. The computational data predicted interaction of the ϒ-phosphate of ATP with Lys 204, which was confirmed by site-directed mutagenesis. The hLAT1-K204Q mutant showed an impaired function and response to ATP. Interestingly, this residue is conserved in several members of the SLC7 family.

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confidence: 99%

ATP modulates SLC7A5 (LAT1) synergistically with cholesterol

Cosco

Scalise

Colas

et al. 2020

Sci Rep

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“…PR was observed in one patient with BTC at the 12 mg/m 2 dose, and the DCR for BTC was 60%. In other cancers, only two patients with colorectal cancer had SD (18). All three PC patients together with one breast and esophagus cancer patients had PD.…”

Section: Resultsmentioning

confidence: 96%

“…Study design and treatment of phase I study. Details of this study, including inclusion and exclusion criteria, trial design, and doseescalation methods have been published previously (18). Briefly, this study was a single-center, open-label, single-arm, first-in-human dose-escalation (3+3 design) phase I study of patients with advanced solid tumors who were refractory to standard chemotherapy.…”

Section: Methodsmentioning

confidence: 99%

“…Following completion of a series of translationally necessary non-clinical studies, we have completed the first-in-human phase I study using the JPH203 formulation. The study consisted of 17 patients with advanced solid tumors (18). As a result, partial response (PR) was achieved in a patient with biliary tract cancer (BTC) and disease control was observed in 3 of 5 patients with BTC.…”

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confidence: 99%

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Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203

Okano

Hana²,

Nagashima

et al. 2020

In Vivo

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Background/Aim: Amino acids are among the most important nutrients for supplying energy and building protein blocks in cancers. L-type amino acid transporter (LAT) 1 is known to play a critical role in cancer growth. We have completed the first-inhuman phase I study using the LAT1-specific inhibitor JPH203. Patients and Methods: We evaluated plasma free amino acids (PFAAs), body mass index (BMI), and efficacy of JPH203 in patients enrolled in the phase I study. Results: LAT1-substrate PFAAs and branched chain amino acids (BCAAs) were higher in patients with biliary tract cancer (BTC) than in those with other cancers. High inhibition of uptake of LAT1-substrate PFAAs was associated with survival. BMI of more than the median was associated with disease control and survival. BCAAs tended to be associated with BMI. Conclusion: BCAAs and BMI are useful predictors of the efficacy of JPH203, which shows promising activity against BTC.

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“…JPH203 was recently evaluated in a first-in-human phase 1 clinical trial (UMIN Clinical Trials Registry UMIN000016546). Okano et al [59] reported among 17 patients with advanced solid tumors, one patient with biliary tract cancer presented a partial response and five patients with biliary tract cancer or Hafliger et al [24] Enomoto et al [26] Barollo et al [27] Shen et al [ www.e-enm.org 231 colorectal cancer presented stable disease. Common treatmentrelated adverse events included malaise, nausea, and a grade 1 or 2 fever.…”

Section: Clinical Application Of Lat1-targeting Agentsmentioning

confidence: 99%

Amino Acid Transporters as Potential Therapeutic Targets in Thyroid Cancer

Enomoto

Hotomi

2020

Endocrinol Metab

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Thyroid cancer cells have a high amino acid demand for proliferation, invasion, and metastasis. Amino acids are taken up by thyroid cancer cells, both thyroid follicular cell and thyroid parafollicular cells (commonly called "C-cells"), via amino acid transporters. Amino acid transporters up-regulate in many cancers, and their expression level associate with clinical aggressiveness and prognosis. This is the review to discuss the therapeutic potential of amino acid transporters and as molecular targets in thyroid cancer.

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First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors

Cited by 99 publications

References 37 publications

ATP modulates SLC7A5 (LAT1) synergistically with cholesterol

ATP modulates SLC7A5 (LAT1) synergistically with cholesterol

Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203

Amino Acid Transporters as Potential Therapeutic Targets in Thyroid Cancer

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