Omomyc mini-protein can be directly and continuously delivered to the brain to prevent glioblastoma in patient-derived xenograft mouse models

Background: Myc is a ‘hot target’ in oncology and implicated in the development of glioblastoma multiforme (GBM), a cancer with a dire prognosis and limited treatment options. Standard of care involves surgery, radiotherapy and treatment of residual tumour with temozolomide. Very few other treatment options exist and they do not significantly affect overall survival, which stands at around 15 months. In a proof of concept, we previously showed Myc inhibition to be a potential strategy against GBM using lentiviral-driven expression of Omomyc, a Myc dominant negative. Here, we address whether Omomyc can be directly administered in vivo as a mini-protein drug to treat GBM. Material and methods: We use the Omomyc mini-protein (OMO-103), currently in early-phase clinical trials for all-comer solid tumours (NCT04808362, sponsored by Peptomyc). Different delivery methods were tested for in vivo treatments. Patient-derived GBM neurospheres were examined in culture and in orthotopic PDX models for their response to Omomyc and to combination with standard of care. Results: We find that intravenous or intranasal delivery shows limited biodistribution to the brain, with some minimal therapeutic efficacy after intranasal treatment. We therefore employed osmotic pumps to directly delivery the mini-protein drug to the brain, avoiding any issues with crossing the BBB and enabling continuous, local administration. In this case, Omomyc prevented the growth of patient-derived GBM orthotopic xenografts. Omomyc reduced proliferation and increased cell death in a panel of patient-derived GBM neurospheres in culture, showing efficacy regardless of their Myc levels, and had additive effects in combination with the standard of care, temozolomide. Conclusions: These results extend the clinical applicability of the Omomyc mini-protein to GBM patients and provides an administration route to deliver the mini-protein drug to this hard-to-reach organ. Conflict of interest: Ownership: LS and MEB are co-founders and shareholders in Peptomyc. Other Substantive Relationships: LS, MEB, JW and LF are shareholders in Peptomyc.