L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. 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. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.Bladder cancer (BC) is the ninth most common malignant tumour worldwide, with 430 000 patients newly diagnosed and 165 000 deaths annually 1 . The pathological type of BC is mainly urothelial cancer ( > 90%) and approximately 70% of patients had non-muscle-invasive BC at diagnosis 2 . These patients have a favorable prognosis with transurethral resection and subsequent intravesical injection therapy, whereas the survival rate of patients with locally advanced and metastatic BC is poor 3 . For metastatic BC patients, platinum-based systematic chemotherapy is the classical treatment, while immunotherapy targeting programmed cell death ligand 1 (PD-L1) blocking antibody was recently approved in Japan 4 . However, drug resistance will occur, and the survival benefit of these agents is not adequate. Their limited efficacy is due to side effects and challenges of drug resistance, leading to treatment failure and require additional treatment options 5 . Therefore, more effective and less toxic therapeutic strategies are needed for the treatment of metastatic BC. Additionally, there are presently no useful diagnostic markers for BC. The urine cytology test is a non-invasive examination, but its sensitivity remains low. Cystoscopy is an essential diagnostic tool but is invasive for patients 5 . Thus, a novel therapeutic approach and biomarker candidates for BC remain a major issue.

Background The inflammatory process has been reported to be involved in the formation and progression of various types of cancer. Recently, a peripheral inflammatory index, combining the derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and the lactate dehydrogenase (LDH) level, was proposed as a useful prognostic marker in advanced nonsmall cell lung cancer. The prognostic value of inflammatory markers in prostate cancer has not been established. We aimed to validate the prognostic significance of this peripheral inflammatory index in metastatic castration‐resistant prostate cancer (mCRPC). Methods Clinical data of 196 mCRPC patients were retrospectively collected from multiple institutions. Clinical factors and inflammatory markers at the development of CRPC, including white blood cell count, absolute neutrophil count, dNLR, neutrophil‐lymphocyte ratio, platelet‐lymphocyte ratio, C‐reactive protein (CRP), and LDH levels, were evaluated. The patients were classified into three groups based on the inflammatory index: Good (low dNLR and LDH), Intermediate (high dNLR or LDH), and Poor (high dNLR and LDH). Overall survival (OS) and cancer‐specific survival after CRPC were analyzed using Cox proportional hazard models and Kaplan‐Meier methods. Results The median age and baseline prostate‐specific antigen level were 75 years and 397.15 ng/mL, respectively. On multivariate analysis, dNLR (≥1.51; hazard ratio [HR] = 1.624; P = .0173), LDH (≥upper limit of normal; HR = 2.065; P = .0004), alkaline phosphatase (≥310 U/L; HR = 2.546; P < .0001), and positive N stage (HR = 1.621; P = .048) were associated with poor OS after CRPC, whereas other inflammatory markers including the NLR were not. The Good inflammatory index group showed significantly longer OS after CRPC compared to the Intermediate and Poor groups, with median survivals of 46.2, 28.9, and 16.6 months, respectively. Conclusions The novel inflammatory index combining dNLR and LDH was a useful prognostic parameter in patients with mCRPC. Our analysis suggested that dNLR emerged as a more valuable prognostic marker than NLR.

L‐type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP‐1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence‐free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.

Background Recent landmark randomized trials (CHAARTED and LATITUDE studies) have highlighted potent upfront therapy for “high‐volume” and “high‐risk” metastatic castration‐naïve prostate cancer (mCNPC). However, treatment response shows racial differences. We aimed to propose a novel definition for “high‐volume” prostate cancer in Asians. Methods We retrospectively pursued 426 patients with de novo mCNPC from multiple institutions between 1999 and 2017. All patients received androgen deprivation therapy alone as initial treatment. We evaluated the number of bone metastases at diagnosis to clarify the clinical significance for progression‐free survival and overall survival (OS). Statistical analyses were conducted using the Mann‐Whitney U test, Cox proportional hazard models, and Kaplan‐Meier methods. Results Median age and prostate‐specific antigen level were 73 years and 266.2 ng/ml, respectively. Median OS was 55.5 months in patients who met the CHAARTED high criteria (vs 33.1 months in the trial). We evaluated 5 thresholds in the number of bone metastases (≥4, ≥6, ≥11, ≥16, and ≥21) to investigate the prognostic values. Patients with ≥11 bone metastases showed the highest HR for OS (2.766). Patients with 11 to 20 bone metastases had a significantly shorter OS than those with ≤10 metastases (P = .0001). We, therefore, proposed modified CHAARTED and LATITUDE high criteria (extending bone metastases ≥11). In multivariate analysis, the modified criteria were the only independent prognostic factors for OS (P = .0272 and P = .042, respectively). Conversely, no significant differences in OS were seen between patients with 1 to 3 bone metastases and 4 to 10 (P = .7513). Conclusion Our exploratory study suggested ≥11 bone metastases as a suitable definition for “high‐volume” prostate cancer in Asians. A larger, prospective study is warranted to verify our findings.

Background To identify the real high-risk group among Japanese de novo metastatic prostate cancer patients who fit CHAARTED or LATITUDE criteria. Methods We retrospectively studied patients who fitted CHAARTED (292 patients) and LATITUDE (294 patients) criteria from Japanese multi-institutions. All patients received androgen deprivation therapy with bicalutamide as an initial treatment. Factors related to overall survival (OS) and progression-free survival were statistically analyzed. Results The median OS was 55.5 months and 60.0 months in patients who met the CHAARTED and the LATITUDE criteria, respectively. In patients who met CHAARTED criteria, lactate dehydrogenase (LDH) (hazard ratio (HR) 2.63, P < 0.0001) and C-reactive protein (CRP) (HR 1.65, P = 0.042) were independent risk factors for OS. In patients who met the LATITUDE criteria, Gleason score (GS) ≥9 (HR 1.77, P = 0.0326) and LDH (HR 2.62, P < 0.0001) were independent risk factors for OS. Modified CHAARTED criteria by adding LDH and CRP showed a significant difference in OS (HR 2.55, P < 0.0001) with a comparative median OS (31.8 months) to placebo of CHAARTED trial (32.2 months). Modified LATITUDE criteria by adding GS ≥9 and LDH showed a significant difference in OS (HR 2.66, P < 0.0001) with a comparative median OS (32.7 months) to placebo of LATITUDE trial (34.7 months). Conclusion Modified criteria may potentially elucidate the true “high volume” and “high risk” patients in the Japanese cohort who require early intensive therapy.