EPEN-20. IDENTIFICATION AND INVESTIGATION OF A NOVEL EPIGENETIC MODULATOR IN POSTERIOR FOSSA EPENDYMOMA, SIRT2 Free

Ependymoma (EPN) is the third most common pediatric central nervous system tumor, associated with poor survival and long-term morbidity. Posterior fossa Group A EPN (PFA) tumors are chemotherapy insensitive and often fatally recur. There is a critical need for new treatments and an untested avenue is targeting of epigenetic modifiers. Our lab has previously shown that the epigenetic suppression of a protein, LDOC1, in PFA drives the NF-kB pathway and constitutive secretion of IL-6. We believe that by targeting specific epigenetic modifiers we can reverse LDOC1 silencing and disrupt this oncogenic pathway in EPN PFA. Using two EPN PFA cell lines, we performed shRNA epigenetic screen identifying key epigenetic regulators including NAD-dependent deacetylase sirtuin 2 (SIRT2). SIRT2 actively inhibits transcription and may silence key tumor suppressing genes. Next, using an epigenetic drug screen we showed that SIRT2 inhibitor AGK2 (2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide) reduced proliferation in cell lines. Inhibition of SIRT2 by AGK2 recovered LDOC1 and down regulated many NF-kB genes. In addition, treatment of an EPN PFA organotype culture with AGK2 re-established LDOC1 and down-regulated IL-6 gene expression. We are now targeting SIRT2 in-vivo in murine sub-cutaneous flank and orthotopic intracranial models of EPN using the compound thiomyristoyl lysine (TM), a SIRT2 inhibitor that is available for in-vivo treatments. These studies suggest that targeting epigenetic modifiers, like SIRT2, can be used as a therapy to target EPN PFA.