Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models

William Senapedis (), Kayleigh M. Gallagher, Elmer Figueroa, Jeremiah D. Farelli, Robert Lyng, J. Graeme Hodgson, Charles W. O’Donnell, Joseph V. Newman, Madison Pacaro, Stephen K. Siecinski, Justin Chen and Thomas G. McCauley
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William Senapedis: Omega Therapeutics
Kayleigh M. Gallagher: Omega Therapeutics
Elmer Figueroa: Omega Therapeutics
Jeremiah D. Farelli: Omega Therapeutics
Robert Lyng: Omega Therapeutics
J. Graeme Hodgson: Omega Therapeutics
Charles W. O’Donnell: Omega Therapeutics
Joseph V. Newman: Omega Therapeutics
Madison Pacaro: Omega Therapeutics
Stephen K. Siecinski: Omega Therapeutics
Justin Chen: Omega Therapeutics
Thomas G. McCauley: Omega Therapeutics

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases.

Date: 2024
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DOI: 10.1038/s41467-024-52202-y

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