Brain cancer is a leading cause of cancer-related mortality in children, with medulloblastoma (MB) being the most common malignant type. Surgery, radio- and chemotherapy are the current standard of care (SoC); however, 30% of patients relapse or develop secondary tumors, and survivors present debilitating neurocognitive impairments from SoC. To address this existing unmet medical need, we must develop novel therapeutic approaches. MYC is a master regulator of cellular processes and one of the most dysregulated proteins in cancer, including MB. When overactivated, it drives tumorigenesis and tumor maintenance, and until recently, MYC has been considered undruggable.

Omomyc is a MYC dominant negative inhibitor, currently in clinical trials for adults with advanced solid tumors as an Omomyc-based mini-protein (OMO-103). With this project, we investigate the use of Omomyc as a potential therapy for pediatric MB. We examine the effect of Omomyc on inhibiting proliferation and self-renewal in vitro in patient-derived MB cells and neural stem cells, and investigate its effects on extending overall survival in vivo. In addition, we perform RNA-sequencing on Omomyc-treated treated MB cells to further investigate the mechanism of action, and we explore MB patient samples transcriptomic datasets to identify combinatorial treatment strategies.

We show that Omomyc selectively targets MB brain tumor initiating cells by impairing proliferation and self-renewal, while sparing the human neural stem cells. Omomyc treatment induces downregulation of MYC regulated genes, cell cycle pathways, and other oncogenic pathways specific to MB. Moreover, the half-maximal inhibitory concentration was maintained between primary and matched SoC-recurrent samples. We further observed a significant survival advantage in our MB patient-derived orthotopic xenograft murine model. Lastly, we identify a suitable synergistic target for combinatorial treatment strategies.

Overall, our work discovers that Omomyc may be a promising therapy for a subset of MB patients with high-MYC expression, particularly at recurrence. Moreover, we have identified a combinatorial treatment strategy with synergistic effect in vitro, and next steps include its validation in vivo. COI: LS is CEO and employee of Peptomyc, a company developing MYC inhibitory peptides. JW and LS are shareholders in Peptomyc.