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Modulation of the MYC oncogene using programmable epigenetic mRNA therapeutics as a novel therapy for hepatocellular carcinoma
Background
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide with a significant unmet medical need. MYC over-expression is associated with aggressive disease in up to ∼70% of HCC. While MYC represents an attractive therapeutic target, it has historically been considered undruggable, due to a lack of a structured binding pocket and tightly regulated expression.
Methods
The MYC gene and its regulatory elements are part of an insulated genomic domain (IGD), a chromatin looping region anchored by CTCF. At Omega, our approach is to epigenetically modulate gene expression pre-transcriptionally utilizing engineered, programmable, mRNA therapeutics called Omega Epigenomic Controllers (OECs), to target IGDs. The development candidate, OTX-2002 is an OEC targeted to the MYC IGD and its activity has been characterized in vitro through MYC mRNA expression, cell viability, and epigenetic changes and in vivo in HCC models by assessing changes in tumor volume, immunohistochemistry (IHC) to detect MYC expression and other biomarkers, and epigenetic alterations. Furthermore, non-human primates (NHPs) were dosed with OTX-2002 to evaluate effects on MYC mRNA expression translationally across species. Additionally, combinations of OTX-2002 with agents used to treat HCC (e.g. tyrosine kinase inhibitors sorafenib and lenvatinib) as well as anti-PD-(L)1 checkpoint inhibitor therapies were tested in vitro along with proteomics analysis (Somalogic) to identify potential synergizing agents.
Results
OTX-2002 was effective at decreasing MYC mRNA, protein and cell viability in HCC cells while sparing normal cells in vitro. In HCC cells, OTX-2002 median EC50 of inhibition is 2 weeks, providing durable MYC mRNA repression. IV delivery of OTX-2002 in vivo at doses of 3 and 6 mg/kg Q5D in a Hep3B subcutaneous model demonstrated significant tumor growth inhibition of 54% and 63%, respectively, with no decrease in body weight. OTX-2002 also showed activity in additional HCC subcutaneous and orthotopic xenograft models. IHC of OTX-2002-treated tumors showed significant down-regulation of MYC with reduced proliferation and increased apoptosis. OTX-2002-induced epigenetic changes were confirmed in extracted tumors. Serially-collected liver biopsies from NHPs treated with OTX-2002 exhibit significant downregulation of MYC mRNA expression 24 hrs (71.9% reduction) and 7 days (75.4% reduction) post-dosing compared to baseline. Combination of OTX-2002 with sorafenib or lenvatinib showed additivity and/or synergy in vitro and in vivo in HCC models. Furthermore, OTX-2002 can decrease surface PD-L1 expression in HCC cells, suggesting a potentially advantageous combination with checkpoint inhibitors. Proteomic analysis also revealed pathways whose inhibition synergizes with OTX-2002’s mechanism of action, including ERK1/2 signaling, NF-kB signaling, and autophagy.
Conclusions
OECs enable pre-transcriptional modulation of the MYC oncogene through precise epigenomic programming of the IGD. Our pre-clinical data show activity both in mice and NHPs. Targeting MYC in this manner may represent a new and potentially effective approach to the treatment of HCC, either as a single agent or in combination with various approved or investigational therapeutics. Omega plans to submit an IND for OTX-2002 in HCC in 1H2022.
Legal entity responsible for the study
Omega Therapeutics.
Funding
Omega Therapeutics.
Disclosures
W. Senapedis: Shareholder / Stockholder / Stock options: Omega Therapeutics; Full / Part-time employment: Omega Therapeutics. K. Gallagher: Honoraria (self): Omega Therapeutics. J. Farelli: Leadership role: Omega Therapeutics, Inc; Shareholder / Stockholder / Stock options: Omega Therapeutics, Inc; Full / Part-time employment: Omega Therapeutics, Inc. C. O'Donnell: Leadership role: Omega Therapeutics; Shareholder / Stockholder / Stock options: Omega Therapeutics; Full / Part-time employment: Omega Therapeutics. J. Newman: Leadership role: Omega Therapeutics. T. McCauley: Leadership role: Omega Therapeutics; Shareholder / Stockholder / Stock options: Omega Therapeutics; Full / Part-time employment: Omega Therapeutics; Officer / Board of Directors: Omega Therapeutics. The author has declared no conflicts of interest.
