Expression of L-Type Amino Acid Transporter 1 as a Molecular Target for Prognostic and Therapeutic Indicators in Bladder Carcinoma - Beyond the Abstract

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids, including leucine, which regulates the mTOR signaling pathway. Our group previously reported the clinical significance of LAT1 in castration-resistant prostate cancer.Here, we studied the expression profile and functional role of LAT1 in bladder cancer.

In collaboration with J-Pharma, we also evaluated the effect of the LAT1 inhibitor: JPH203. This drug was tested in a Phase I clinical trial and safety were demonstrated in patients with advanced solid tumors refractory to standard therapy.However, urological tumors were not included in the trial. 

In the current study, LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK/Erk, AKT, p70S6K, and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (p=0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression.

Based on this finding, targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment. We are planning Phase II clinical trials in advanced urological cancers and hoping to provide positive results in the near future.

Written by: Shinichi Sakamoto, MD, PhD, Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan

References:

  1. Xu, Minhui, Shinichi Sakamoto, Jun Matsushima, Toru Kimura, Takeshi Ueda, Atsushi Mizokami, Yoshikatsu Kanai, and Tomohiko Ichikawa. "Up-regulation of LAT1 during antiandrogen therapy contributes to progression in prostate cancer cells." The Journal of urology 195, no. 5 (2016): 1588-1597.
  2. Okano, Naohiro, Kirio Kawai, Yoshiya Yamauchi, Takaaki Kobayashi, Daisuke Naruge, Fumio Nagashima, Hitoshi Endou, and Junji Furuse. "First-in-human phaseⅠstudy of JPH203 in patients with advanced solid tumors." (2018): 419-419.
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