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Clinical Trial
. 2020 Sep-Oct;34(5):2595-2606.
doi: 10.21873/invivo.12077.

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

Naohiro Okano  1 , Kiyomi Hana  2 , Daisuke Naruge  3 , Kirio Kawai  3 , Takaaki Kobayashi  3 , Fumio Nagashima  3 , Hitoshi Endou  2 , Junji Furuse  3
Affiliations
Clinical Trial

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

Naohiro Okano et al. In Vivo. 2020 Sep-Oct.

Abstract

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-in-human 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.

Keywords: JPH203; L-type amino acid transporter; amino acids; biliary tract cancer; body mass index.

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Conflict of interest statement

Okano N. received personal fee from J-Pharma. Hana K. received salary from J-Pharma. 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 grant and personal fee from J-Pharma. The other Authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Efficacy of JPH203 due to L-type amino acid transporter 1 (LAT1)-substrate inhibition. (A) Progression-free survival. (B) Overall survival. The degree of inhibition of uptake of the LAT1-substrate plasma free amino acids (PFAAs) was divided into high and low inhibition groups by the median. Black line, high inhibition group. Dotted line, low inhibition group. CI: Confidence interval.
Figure 2
Figure 2. Effect of JPH203 on plasma free amino acids (PFAAs) in pancreatic cancer. (A) Total amino acids (AAs). (B) L-type amino acid transporter 1 (LAT1) substrate AAs. (C) non-LAT1 substrate AAs.
Figure 3
Figure 3. Effect of JPH203 on plasma free amino acids (PFAAs) in biliary tract cancer. (A) Total amino acids (AAs). (B) L-type amino acid transporter 1 (LAT1) substrate AAs. (C) non-LAT1 substrate AAs.
Figure 4
Figure 4. Efficacy of JPH203 in High- and Low-body mass index (BMI) groups. (A) Progression-free survival. (B) Overall survival. BMI was divided into a High-BMI group and a Low-BMI group by the median. Black line, High-BMI group. Dotted line, Low-BMI group. CI: Confidence interval.
Figure 5
Figure 5. Correlation between amino acids and body mass index (BMI). (A) Correlation between the L-type amino acid transporter 1 (LAT1)-substrate plasma free amino acid (PFAA) levels and BMI. (B) Correlation between the plasma levels of branched chain amino acids (BCAAs) and BMI.
Figure 6
Figure 6. Cancer type and L-type amino acid transporter 1 (LAT1) immunohistochemical staining. (A-F). Colorectal cancer; (G-K) Biliary tract cancer; (L-O) Pancreatic cancer; (P) Breast cancer; (Q) Esophageal cancer. Panel D, E, N, O, and P show magnifications of 200×. The others show magnifications of 400×.
Figure 6
Figure 6. Cancer type and L-type amino acid transporter 1 (LAT1) immunohistochemical staining. (A-F). Colorectal cancer; (G-K) Biliary tract cancer; (L-O) Pancreatic cancer; (P) Breast cancer; (Q) Esophageal cancer. Panel D, E, N, O, and P show magnifications of 200×. The others show magnifications of 400×.
Figure 7
Figure 7. Relationship between Km values of L-type amino acid transporter 1 (LAT1) and LAT1-substrates plasma free amino acids (PFAAs). Amino acids (AAs) surrounded by squares denote branched chain amino acids (BCAAs).
See this image and copyright information in PMC

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