Omomyc is finally in the clinic. What a journey!

MYC is the most deregulated oncogene in human cancer, where it directs transcriptional programs that allow cancer cells to thrive and survive therapies. Despite being a most wanted target in cancer treatment, it has been long considered undruggable.
Published in Cancer
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The perception of MYC as an undruggable target is mainly due to its intrinsically disordered nature [1]. That means that MYC is a protein that changes shape all the time in solution, making it particularly difficult to design an inhibitor against it using standard small molecule approaches. In fact, these approaches resemble the design of a key for a lock, but, in that comparison, MYC represents a lock that continually changes shape, making most keys useless or not very specific for it. Our approach has been different from the beginning: we never used small molecules and preferred instead to rely on mini-proteins, which have a much larger interaction surface with MYC. In particular, we focused on the possibility of mimicking MYC’s natural binding partner, MAX, to build a bait that could force MYC to assume a defined structure (the one needed to bind MAX) and trap it in an inactive form. This bait is Omomyc, a mini-protein of 91 aminoacids that we first published in 1998 [2]. Omomyc forms heterodimers with MYC that are not able to bind DNA, but also homodimers and heterodimers with MAX that, instead, occupy DNA as inactive protein complexes, shutting down the transcription of MYC/MAX target genes. Omomyc was first used in cells as a MYC dominant negative and showed therapeutic impact against different transformed cells, while only slowing down proliferation of normal cells [3]. Although interesting, this first observation was mostly dismissed by the MYC community as being too simplistic and not representative of in vivo models [4]. Then, Omomyc was used in mouse models of cancer, where we showed its extraordinary therapeutic window and dramatic therapeutic impact, independently of the tissue of origin of the tumors or even their driving lesions [4-9]. These findings changed the perception of MYC as a potentially druggable target, but were not sufficient to promote Omomyc to a status of likely drug candidate, since the field largely continued to consider it a mere proof of concept and unsuitable for further drug development [4]. It was only when we showed that the purified Omomyc mini-protein had unexpected cell-penetrating properties [10] that the possibility of its development into a viable pharmacological treatment became finally feasible. And so, more than 20 years after its first publication, Omomyc finally reached clinical trials in 2021, with the drug name "OMO-103". The clinical trial was a Phase I study in all-comers solid tumors that was completed in October 2022 (and just published in Nature Medicine [11]), in which the compound showed safety and clinical signs of drug activity and target engagement. With this milestone, Omomyc is officially the first direct MYC inhibitor to have ever reached this clinical development stage. 

The encouraging results of the Phase I have prompted the beginning of a new trial, currently ongoing, in metastatic pancreatic ductal adenocarcinoma patients, where OMO-103 is combined with standard of care chemotherapy. 

Omomyc's journey so far has been somewhat tortuous, complicated by the choice of an "undruggable" target and the need to pioneer a first-in-modality mechanism of action based on a mini-protein therapeutic. Its new road in the clinic has just begun, but making it this far gives us great hope that its therapeutic application will see it trailblazing MYC inhibition in oncology and beyond. The laboratory tool that we developed over two decades ago has never ceased to surprise and teach, and I am confident we still have a lot to learn from it.

 

 References

  1. Dang, C.V., et al., Drugging the 'undruggable' cancer targets. Nat Rev Cancer, 2017. 17(8): p. 502-508.
  2. Soucek, L., et al., Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene, 1998. 17(19): p. 2463-72.
  3. Soucek, L., et al., Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res, 2002. 62(12): p. 3507-10.
  4. Masso-Valles, D. and L. Soucek, Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc. Cells, 2020. 9(4).
  5. Annibali, D., et al., Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat Commun, 2014. 5: p. 4632.
  6. Sodir, N.M., et al., Endogenous Myc maintains the tumor microenvironment. Genes Dev, 2011. 25(9): p. 907-16.
  7. Soucek, L., S. Nasi, and G.I. Evan, Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ, 2004. 11(9): p. 1038-45.
  8. Soucek, L., et al., Modelling Myc inhibition as a cancer therapy. Nature, 2008. 455(7213): p. 679-83.
  9. Soucek, L., et al., Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev, 2013. 27(5): p. 504-13.
  10. Beaulieu, M.E., et al., Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy. Sci Transl Med, 2019. 11(484).
  11. Garralda, E., et al., MYC-targeting by OMO-103 in solid tumours: a phase 1 trial. Nature Medicine. doi: 10.1038/s41591-024-02805-1.

 

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