# Targeting Glutamine Transporters as a Novel Drug Therapy for Synovial Sarcoma

## TL;DR

This study shows that blocking glutamine transport with V9302 could be a new treatment for synovial sarcoma, a hard-to-treat cancer.

## Contribution

The study identifies ASCT2 as a novel therapeutic target in synovial sarcoma and demonstrates the efficacy of its inhibition with V9302.

## Key findings

- ASCT2 is highly expressed in synovial sarcoma and is crucial for cancer cell growth.
- V9302 inhibits ASCT2, reduces tumor growth, and activates apoptosis in synovial sarcoma cells.
- V9302 treatment suppressed the AKT/mTOR pathway and was effective in both in vitro and in vivo models.

## Abstract

Synovial sarcoma is an aggressive cancer with limited treatment options. This study found that synovial sarcoma cells rely heavily on glutamine for growth. The glutamine transporter ASCT2 was highly expressed in patient samples. Blocking ASCT2 with the inhibitor V9302 reduced cancer cell growth, triggered apoptosis, and suppressed the AKT/mTOR signaling pathway in both in vitro and in vivo models, without causing serious side effects. These findings suggest that targeting glutamine metabolism through ASCT2 inhibition could be a promising new treatment strategy for synovial sarcoma.

Background/Objectives: Synovial sarcoma (SS) is a malignant soft tissue neoplasm with good outcomes in adolescents with localized tumors, but poor outcomes in older adults and in advanced or metastatic cases. Targeting cancer metabolism, such as glutamine metabolism, is a promising therapeutic strategy. In this study, we investigated glutamine dependency in SS and assessed the therapeutic potential of inhibiting the glutamine transporter ASCT2 using V9302. Methods: Immunohistochemistry (IHC) was used to evaluate ASCT2 expression in SS and liposarcoma (LPS) specimen. The effects of glutamine deprivation and V9302 were examined in a SS cell line (HS-SY-II), patient-derived SS cells (SSH1), and a normal cell line (HEK293). Cell viability, apoptosis, and protein expression were assessed using the CCK-8 assay, flow cytometry, and Western blotting, respectively. The therapeutic efficacy of V9302 was evaluated in a xenograft model using IHC. Results: ASCT2 expression was elevated in SS tumor tissues compared with adjacent normal tissues and LPS specimens. Both the HS-SY-II cell line and SSH1 cells exhibited strong glutamine dependency for proliferation. V9302 selectively reduced HS-SY-II cell viability by suppressing the AKT/mTOR signaling pathway and inducing apoptosis via caspase-3 activation, with minimal effects on control cells. In vivo, V9302 administration significantly inhibited tumor growth without inducing systemic toxicity, and IHC of the treated tumors confirmed the suppression of the mTOR pathway and induction of apoptosis. Conclusions: Our findings suggest that SS is a glutamine-dependent malignancy and validate ASCT2 as a promising therapeutic target. The ASCT2 inhibitor V9302 demonstrated therapeutic efficacy both in vitro and in vivo, supporting its potential as a therapeutic agent for SS.