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Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

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.

SUBMITTER: Beaulieu ME

PROVIDER: S-EPMC6522349 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

Beaulieu Marie-Eve ME Jauset Toni T Massó-Vallés Daniel D Martínez-Martín Sandra S Rahl Peter P Maltais Loïka L Zacarias-Fluck Mariano F MF Casacuberta-Serra Sílvia S Serrano Del Pozo Erika E Fiore Christopher C Foradada Laia L Cano Virginia Castillo VC Sánchez-Hervás Meritxell M Guenther Matthew M Romero Sanz Eduardo E Oteo Marta M Tremblay Cynthia C Martín Génesis G Letourneau Danny D Montagne Martin M Morcillo Alonso Miguel Ángel MÁ Whitfield Jonathan R JR Lavigne Pierre P Soucek Laura L

Science translational medicine 20190301 484

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 variou ...[more]

PMID: 30894502

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Project description:BACKGROUND:Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. METHODS:Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15?mg in 0.3?ml, 35?mg in 0.7?ml, or 40?mg in 0.4?ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for ?-smooth muscle actin (ACTA2). Secondary outcomes included levels of ?-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). FINDINGS:We recruited 28 patients, 8 assigned to the 15?mg, 12 to the 35?mg and 8 to the 40?mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of ?-SMA protein expression in patients treated with 40?mg adalimumab (1.09?±?0.09?ng per ?g of total protein) were significantly lower (p?=?0.006) compared to placebo treated patients (1.51?±?0.09?ng/?g). The levels of procollagen type I protein expression were also significantly lower (p?<?0.019) in the sub group treated with 40?mg adalimumab (474?±?84?pg/?g total protein) compared with placebo (817?±?78?pg/?g). There were two serious adverse events, both considered unrelated to the study drug. INTERPRETATION:In this dose-ranging study, injection of 40?mg of adalimumab in 0.4?ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of ?-SMA and type I procollagen proteins at 2?weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40?mg adalimumab in 0.4?ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease. FUNDING:Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Dataset Information

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

Publications

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

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