EXTH-94. Can the tumor microenvironment attenuate drug efficacy? Potential vulnerabilities of LAT1 inhibitors

Abstract BACKGROUND Many cancers demonstrate upregulated amino acid transport. In glioblastoma (GBM), evidence for upregulated amino acid flux includes high signal on amino acid PET imaging, increased expression of LAT1 (L-type amino acid transporter 1), and elevated extracellular amino acid levels via microdialysis. LAT1-targeted therapies have shown antitumor effects in certain cancer models by restricting essential amino acid supply and inhibiting the mTOR pathway, but their utility for GBM remains unknown. In this study, we evaluated impacts of a competitive LAT1 inhibitor, nanvuranlat, and a non-competitive inhibitor, JPH034 against glioblastoma. METHODS Murine (CT-2A, GL261) and human (GBM6, GBM39) GBM cell lines were tested under varying concentrations of nanvuranlat or JPH034. The competitive impacts of added essential amino acids, serum, and albumin were evaluated in vitro. Survival impacts were evaluated in an intracranial CT-2A glioma model. RESULTS Supplementing essential amino acids in vitro significantly decreased tumor cell sensitivity to nanvuranlat but did not change the IC50 of JPH034. Conversely, supplementing serum or albumin significantly reduced tumor cell sensitivity to JPH034 but did not change the IC50 of nanvuranlat. These findings were reproducible in all human and murine cell lines tested. In the intracranial mouse model, JPH034 treatment prolonged median overall survival from 16 days in the control group to 18.5 days, representing a 2.5-day extension (p = 0.060). CONCLUSION The antitumor effects of nanvuranlat and JPH034 on glioma cells in vitro, are influenced by concentrations of essential amino acids and albumin. Specifically, amino acids decreased impact of the competitive inhibitor (nanvuranlat) while albumin decreased impact of the non-competitive inhibitor (JPH034). These results suggest that the composition of the tumor microenvironment, which is impacted by BBB-disruption within GBM may differentially attenuate the therapeutic efficacy of certain drugs including LAT1 inhibitors.