MODL-27. MEK INHIBITION WITH TRAMETINIB SLOWS PROGRESSION OF MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR IN ORTHOTOPIC XENOGRAFT MURINE MODEL

BACKGROUND: Combination of surgery, chemotherapy, autologous transplantation, irradiation constitutes treatment of CNS embryonal-cell tumors (Medulloblastoma-MBL, atypical teratoid rhabdoid tumor-AT/RT). Targeted agents to improve survival and decrease side effects are necessary. We hypothesize that inhibiting MAPK pathway in MBL and AT/RT may be beneficial. METHODS: IHC(pERK) was performed on clinical tumors. Trametinib(MEK inhibitor) was tested on MBL(UW228, D283, DAOY); AT/RT(CHLA06, BT12) cell-lines. Luminescent cell-viability assay was done(72 hrs) and with crystal violet assay(10 days). Orthotopic, xenografts of MBL and AT/RT were made in NOD-Scid gamma mice. Mice were given Trametinib daily by gavage for 6 weeks(0.6mg/kg b.w). Western blot was performed on protein from cell lines and tumor xenografts incubated with Trametinib. H&E staining was done on murine tumors. RESULTS: AT/RT(48%) and MBL(57%); Anaplastic(50%), Desmoplastic(40%), Classic(38%); Group 4(66%), Group 3(20%), SHH(55%), WNT(0%) showed presence of pERK(clinical samples). In-vitro, Trametinib completely abrogated the phosphorylation of ERK at 125nM in AT/RT and 50nM in MBL. The IC50 after 10 days exposure was 10nM for AT/RT and 35nM for MBL. Trametinib treated mice showed delay in tumor growth and significant survival advantage in both AT/RT (p=0.00336) and MBL (p=0.0069). Murine tumors showed decreased proliferation (H&E). CONCLUSION: Trametinib decreased cell proliferation, increased survival in our murine model in both MBL and AT/RT. Pre-clinical results indicate benefits in subgroups of AT/RT and MBL with active MAPK pathway.