DIPG-09. TRX-E-009-1 IS A NOVEL AND A POTENT THERAPEUTIC AGENT FOR DIFFUSE INTRINSIC PONTINE GLIOMAS

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumours. They mostly affect young children and, as there are no effective treatments, almost all will succumb to the disease within 12 months. TRX-E-009-1 is a novel anti-cancer agent in preclinical development with broad anti-cancer activity. Ecto-NOX disulfide-thiol exchanger 2 (ENOX2) is the putative target of benzopyran molecules, a family to which TRXE-009-1 belongs. We have found that ENOX2 is significantly over-expressed in our panel of patient-derived DIPG cell lines, while it is completely absent from normal astrocytes. Given these differences in expression, we examined the anti-tumour activity of TRX-E-009-1 against our DIPG neurosphere cultures and found striking tumour specific activity with an IC50 ranging from 20–100 nM with no activity against normal human astrocyte cells (NHAs). We showed that TRX-E-009-1 exerts its anti-proliferative effect through the induction of apoptotic pathways with marked increases in the levels of cleaved caspase 3 and cleaved PARP. TRX-E-009-1 also suppresses the expression of PDGFR-α while enhancing histone H3.3K27me3 methylation. In a DIPG orthotopic model, survival of mice treated with TRX-E-009-1 was significantly increased compared with controls (median survival control 70.5 days vs. 97 days TRX-E-009-1 treated; P = 0.0029). Further, in vitro, the combination of TRX-E-009-1 with a compound currently under clinical investigation against glioma significantly improved cytotoxic activity against DIPG neurospheres. Our findings indicate that TRX-E-009-1 represents a novel, potentially effective therapy for children with DIPG.