The five year survival of children with refractory or relapsed neuroblastoma (NBL), often with MYCN amplified tumors, is only about 10%, and the outcome for this subset of patients has shown no improvement over the last 30 years, thus new treatment approaches are urgently needed. We propose to exploit a newly discovered function of the tumor suppressor PP2A in promoting transcriptional pausing of RNA polymerase II as a novel anti-cancer mechanism which underlies transcriptional addiction, an acquired reliance on the continuous activity of an oncogenic transcription program in MYCN amplified NBL. This is an, as yet, unexploited therapeutic vulnerability of MYCN amplified NBL, and it is likely to be synergistic with the known PP2A-B56 mediated destabilization of N-Myc. The lead compounds are proprietary small molecule allosteric activators of PP2A. The research objectives are to establish activity in cellular models of MYCN amplified NBL and demonstrate effects on (i) transcriptional function via RNAPII CTD phosphorylation, (ii) N-MYC expression and stability at the protein level, and NMYC gene transcription; and (iii) expression of the endogenous PP2A inhibitor CIP2A at the protein and transcriptional levels. The company will also assess the efficacy of a lead compound in a PDX mouse model of MYCN amplified NBL.