Abstract 3602: JHU395, a nervous tissue penetrant glutamine antagonist, restricts growth of malignant peripheral nerve sheath tumor with inhibition of nucleotide synthesis

Malignant peripheral nerve sheath tumor (MPNST) is a sarcoma that occurs in ~10% of patients with neurofibromatosis type I (NF1). Incomplete surgical resection at diagnosis leads to a 4-year event-free survival rate of 30 micromolar). JHU395 delivered GA to MPNST cells with >4-fold higher cell-to-plasma ratio compared to native GA and maintained ~2.5-fold higher tumor-to-plasma GA levels in vivo. Mice treated with JHU395 had >40% smaller mean tumor volume compared to controls with no overt toxicity. Quantitiative bioanalysis revealed that JHU395 treated tumors had >60% higher glutamine levels compared to controls 30 minutes after oral dosing. In vivo flux analysis demonstrated that JHU395 preferentially affects tumor glutamine utilization for nucleotide synthesis, while glutamine-derived substrates for the citric acid cycle appear unaffected. In summary, JHU395 inhibits growth of MPNST with inhibition of glutamine utilization in nucleotide synthesis