Omomyc downregulates MYC transcriptional signature in preclinical models of solid tumours and shows long half-life in tumour tissue

Background: The expression and function of the MYC family of oncoproteins are tightly regulated in normal cells, but it becomes deregulated in up to 70% of human cancers through a variety of mechanisms, functioning as a master modulator of the cancer transcriptome. Despite the broad therapeutic utility anticipated for a clinical MYC inhibitor, MYC remains considered undruggable, and so far, no direct MYC inhibitor has been approved for clinical use. Omomyc is a first-in-modality recombinant mini-protein that entered into a Phase I/IIa clinical trial in March 2021 to evaluate its safety and efficacy. Omomyc relies on a unique mechanism of action (MoA), acting as a dominant-negative of the MYC protein: it competes with the MYC/MAX dimers by forming homo- and heterodimers and sequestering MYC away from its target genes on DNA. In this work, we aimed at describing the transcriptional reprogramming exerted by Omomyc supporting target engagement in preclinical models of various solid tumours. Materials and methods: We used 2 cell lines of each lung cancer (A549, H441), colorectal cancer (SW480, DLD-1) and breast cancer (MDA-MB-231, MX-1). We treated the cells in vitro with 10, 20 and 30 μM of Omomyc for 24 and 120 h and analysed cell proliferation and gene expression by RNAseq. We also assessed Omomyc’s efficacy at 25, 50 and 75 mg/kg after 3 weeks of intravenous (iv), weekly treatments in subcutaneous xenograft mouse models of each cell line. Finally, we analysed the transcriptome of in vivo tumours by RNAseq after 24 h or 22 days of treatment. Importantly, to characterise the PK/PD relationship, we quantified the amount of functional Omomyc present in tumour tissue homogenates (fresh-frozen and paraffin-embedded) and serum of the treated mice using a targeted proteomic approach. Results: All the cell lines treated with Omomyc showed the shutdown of MYC transcriptional signature, both at 24 and 120 h, confirming the on-target activity in vitro. Moreover, all the Omomyc-treated xenografts showed reduced tumour growth and MYC transcriptional shutdown in vivo as well. Importantly, quantification of functional Omomyc revealed that 2 h after iv administration, higher concentrations of the drug were reached in the tumours compared to serum, and persisted at least 4 times more concentrated in the tumour tissue at 72 h after dosing. In accordance to Omomyc’s MoA, there was no correlation between MYC levels and the response to MYC inhibition. Conclusions: Our results show evidence of the long-lasting half-life of functional Omomyc in tumour tissues, in vivo target engagement and therapeutic utility of this pan-MYC inhibitor in lung, colon and breast cancer models. They also shed light on potential predictive biomarkers of response to Omomyc treatment, bringing insights for the clinical path fulfilment of this cutting-edge therapeutic modality. Conflict of interest: Other Substantive Relationships: S. Martínez-Martín, S. López-Estévez, H. Thabussot, V. Castillo Cano are employees of Peptomyc S.L. L. Foradada and S. Casacuberta-Serra are employees and shareholders of Peptomyc S.L. L.Soucek and M-E. Beaulieu are co-founders and shareholders of Peptomyc S.L.