Peptomyc S.L., Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Sci Transl Med. 2019 Mar 20;11(484). doi: 10.1126/scitranslmed.aar5012.
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.
长期以来，抑制 MYC 一直被认为是不可行的，尽管它在人类癌症中的关键作用使其成为治疗干预的理想靶点。其被认为不可成药的一个原因是担心在正常组织中产生灾难性的副作用。然而，我们之前设计了一种名为 Omomyc 的 MYC 显性负性形式，并利用其条件性转基因表达在体外和体内抑制 MYC 功能。Omomyc 对 MYC 的抑制在各种癌症小鼠模型中产生了强大的治疗效果，只引起轻微、可耐受和可逆的副作用。然而，到目前为止，Omomyc 仅被认为是一个原理验证。与这种先入为主的观念相反，在这里，我们表明纯化的 Omomyc 小蛋白本身可以自发地穿透癌细胞，并有效地干扰其中的 MYC 转录活性。Omomyc 小蛋白在具有不同致癌突变谱的非小细胞肺癌的各种实验模型中的疗效确立了其在直接组织递送和全身给药后的治疗潜力，为 Omomyc 小蛋白是一种有效的 MYC 抑制剂，值得临床开发提供了证据。
