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A mini-protein with mighty effects
The transcription factor MYC is an oncogene that has been implicated in a variety of cancers but has proven very difficult to target therapeutically. Omomyc mini-protein is a dominant-negative form of MYC that is used to inhibit MYC for research purposes but was thought to be too unwieldy for in vivo therapy. However, Beaulieu et al. discovered that Omomyc can penetrate into cancer cells in vitro and in vivo. The authors used mouse models of non–small cell lung cancer to demonstrate the effectiveness of Omomyc delivered intranasally or intravenously, alone or combined with chemotherapy, setting the stage for potential clinical development of this mini-protein.
Abstract
Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non–small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.
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