AT-04TOWARDS AN EPIGENETIC THERAPY FOR RHABDOID TUMORS -IN VITRO RESULTS FOR THE EPIGENETIC MODULATORS RESMINOSTAT AND 4SC-202

AT-04. TOWARDS AN EPIGENETIC THERAPY FOR RHABDOID TUMORS -IN VITRO RESULTS FOR THE EPIGENETIC MODULATORS RESMINOSTAT AND 4SC-202 Hella Kohlhof2, Tanja Wulff2, Daniel Vitt2, and Michael Fruehwald1; Children’s Hospital Augsburg, Augsburg, Germany; 4SC AG, Martinsried, Germany Among others histone deactyleases 1 and 2 (HDAC1, 2) are overexpressed across all molecular subgroups of AT/RT. Resminostat is an orally available inhibitor of HDAC classes I and IIb; whereas 4SC-202 is a combined inhibitor of HDAC1/2/3 and the lysine specific demethylase LSD1. Additionally, 4SC-202 inhibits the SMO-independent HH signaling which is often aberrantly activated in AT/RT. Both inhibitors have proven tolerability and efficacy in phase I or II trials in adults. Their toxicity profile appears to be favorable while maintaining targeting efficacy. Proliferation and viability of cell lines G401 (RTK), A204 (MRT) and CHLA-02 (AT/ RT) were evaluated by crystal violet staining and MTT, spheroid and colony formation assays. Expression of genes associated with the phenotype of rhabdoid tumors such as SMARCB1, CDKN1C, MYC, CyclinD1 and HHIP was examined by qRT-PCR. As comparative HDACi Vorinostat, Panobinostat, Entinostat, Mocetinostat and Ricolinostat were tested. Resminostat and 4SC-202 exhibited a dose dependent inhibition of proliferation and viability of RT cells. Inhibition of the capacity for clonogenic growth was demonstrated. Gene expression data are currently evaluated. Rhabdoid tumors as paradigmatic epigenetic malignancies appear to be the optimal foci for drugs targeting the epigenetic scaffolding of tumor cells. The epigenetic modulators Resminostat and 4SC-202 warrant further testing in clinical trials in children with rhabdoid tumors. Likely combinatorial therapy will be needed to prove a significant effect on outcome for affected high-risk patients. Neuro-Oncology 18:iii1–iii6, 2016. doi:10.1093/neuonc/now065.3 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.