(P 145) EXPLORING L-TYPE AMINO ACID TRANSPORTER 1 (LAT1) AS A DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)

Objective: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that frequently arise from benign plexiform neurofibromas (PN). Approximately half of MPNST are associated with Neurofibromatosis type 1 (NF1). Despite partial elucidation of the molecular mechanisms underlying MPNST, diagnosis remains challenging, and prognosis is poor. Previously, we found that MPNST cells have elevated βIII-spectrin, a cytoskeletal protein involved in cell morphology and regulation of transporters, including L-type Amino Acid Transporter 1 (LAT1). LAT1 facilitates transport of large neutral amino acids and is upregulated in other cancer types. Furthermore, LAT1-mediated transport can be imaged by positron emission tomography (PET) with the labeled amino acid [18F]-Fluorodopa ([18F]-FDOPA). Our objective is to investigate LAT1 as a diagnostic marker and therapeutic target for MPNST.

Methods: Gene and protein expression were determined by qPCR and WES western analysis, respectively. The effect of shRNA knockdown of LAT1 in MPNST cells was assessed using IncuCyte proliferation assays as well as multiple MPNST mouse models. Tumor uptake of [18F]-FDOPA, primarily transported by LAT1, in MPNST PDX tumors was assessed using PET/CT imaging.

Results: LAT1 was expressed in MPNST (n=14) but not benign PN tissues (n=6). Additionally, in human and murine MPNST cells, shRNA-mediated knockdown of LAT1 suppressed proliferation of MPNST cells in vitro as well as tumor growth in vivo in three mouse xenograft tumor models. In a subcutaneous tumor growth model, intratumor injection of shLAT1 lentivirus reduced tumor volume to approximately 50% of control. Furthermore, uptake of [18F]-FDOPA by LAT1 in MPNST PDX tumors was detected by PET/CT imaging. WU-356 PDX tissues exhibited high LAT1 expression as well as increased uptake of [18F]-FDOPA in tumors. Conversely, PET imaging showed significantly lower uptake of [18F]-FDOPA in LAT1 knockdown tumors (p< 0.05). This initial data provides evidence of the utility of PET imaging with the radiotracer [18F] FDOPA as a diagnostic tool for MPNST imaging.

Conclusion: These results suggest that LAT1 promotes the growth and survival of MPNST cells. In addition, these findings demonstrate the potential use of LAT1 and the radiotracer [18F]-FDOPA as a diagnostic biomarker in the management of MPNST.