CBMT-09. THERAPEUTIC EFFECT OF INDUCTION OF POLYGLUTAMYLATION IN HIGH-DOSE METHOTREXATE THERAPY TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract BACKGROUND Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. Methotrexate (MTX) incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. In this study, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status and evaluated the combined effect of MTX and the drugs which upregulated polyglutamylation of MTX. METHODS Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma cell lines were used for in vitro and in vivo experiments. The association of polyglutamylation and the response to MTX with LV rescue was assessed in these cell lines. Histone-deacetylase inhibitor (HDACI) has been reported to induce polyglutamylation by elevating folpolyglutamate synthetase (FPGS) expression, so the effects of HDACIs on polyglutamylation were evaluated. Combined effects of MTX and HDACI were evaluated by cell viability assay and xenograft mouse models. RESULTS The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). The combined effect of MTX and HDACI was significantly enhanced in cell viability assay in vitro (p< 0.05), in subcutaneous (p< 0.001) and intracranial tumor xenografts (p< 0.001). CONCLUSION These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combined therapy with HD-MTX and HDACIs might represent a promising treatment for HD-MTX resistant intractable PCNSL.