MOLECULAR & CELLULAR ONCOLOGY 2019, VOL. 6, NO. 5, e1618178 (3 pages) https://doi.org/10.1080/23723556.2019.1618178 AUTHOR’S VIEWS Finding MYCure a a,b,c,d Marie-Eve Beaulieu and Laura Soucek a Peptomyc S.L., Edifici Cellex, Barcelona, Spain; bVall d’Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d’Hebron, Barcelona, Spain; c Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; dDepartment of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain ABSTRACT ARTICLE HISTORY Inhibiting the nuclear protein MYC involved in the majority of human cancers has long been considered Received 30 April 2019 an impossible mission and several technical challenges have discouraged the development of MYC Revised 8 May 2019 inhibitory strategies. Nevertheless, in our recent publication in Science Translational Medicine “Intrinsic Accepted 9 May 2019 cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy”, we KEYWORDS demonstrate for the first time the feasibility of pharmacological MYC inhibition in vitro and in vivo MYC; OMOMYC; NSCLC; using an Omomyc-based mini-protein. peptide therapeutic; mini- protein Text clinically established the feasibility of pharmacologically tar- geting MYC – not only a well-characterized central node in Let’s be honest: working in cancer research is both a blessing cancer but also a nuclear transcription factor and intrinsically and a curse. On one hand, one feels that we are fighting the disordered protein2 – by making use of a cell-penetrating good fight, looking for the ideal cancer drug that will poten- polypeptide called Omomyc. tially spare the lives of millions of people; on the other, the MYC is known to be deregulated in the majority of cancers, fight seems unfair, against an impossible enemy that displays either following gene amplification or mutation of many upstream the capacity to develop resistance to whichever therapy we signalling pathways – the Kirsten RAt Sarcoma GTPase (com- come up with. Can we do better than that? monly known as KRAS), Phosphatidylinositol-3 Kinase (PI3K), The answer to this question might be found by redefining our Wingless-related integration protein (better known as WNT), concept of the ideal cancer drug. We can all agree, for example, etc. – which can lead to steady, non-stop MYC function.2 Many that such a drug should target a non-redundant function in studies have now clearly established the therapeutic utility of cancer cells, ideally essential only for tumor cells but not for targeting MYC for cancer treatment.3 However, as MYC is essen- normal tissues. However, the majority of our targets so far are tial during embryonic development and for normal function of instead in the most redundant compartments of cells and path- proliferative tissues, dramatic side effects were expected from its ways that can quickly rewire to compensate for our attacks. complete inhibition. Previous strategies to drug MYC have Current approaches should not be dismissed and it is apparent attempted to inhibit it at many levels, from transcription to that, in many instances, they have led to a significant degree of translation, or even protein stability.3 In the few cases in which success, especially in personalized medicine, which is clearly some of these attempts have reached the clinic, they have been effective at least in a certain percentage of patients. discontinued due to evidence of toxicity. Interestingly, though, Nevertheless, these approaches can be complemented by alter- this clinical toxicity did not seem to arise directly from the MYC natives. Novel opportunities, for instance, might lie in the iden- blockade, but because of the use of ineffective inhibitory strategies tification of central, less evolutionarily degenerate nodes in and lack of specificity for the target. In this respect, our proposed cancer, which might be non-redundant and offer unprecedented therapeutic mini-protein approach is different. therapeutic strategies not yet explored. Some of these functions The MYC transcription factor is composed of a DNA binding might be identified, for example, in the nuclei of cells (a com- and dimerization domain (DBD) and a transactivation domain partment less accessible to standard drugs) and fall into the (TA). In order to function, MYC must form heterodimers with the category of transcription factors, master regulators of the onco- MYC associated factor X (better known as MAX), its obligate genic programs that can contribute to the cancer phenotype. partner, which enables binding to Enhancer box (E-box) DNA Among those, an even more challenging group is represented by sequences. We previously designed Omomyc, a MYC-dominant intrinsically disordered proteins, which lack a defined three- negative consisting of the DBD of MYC containing four amino dimensional structure amenable to attack by canonical small acidic mutations. Thanks to these mutations and its altered dimer- molecule inhibitors. ization properties compared to the wild type DBD of MYC, But are these challenges sufficient to dismiss these targets Omomyc is able to both inhibit MYC/MAX interaction and as “undruggable”? Our answer is definitely not. In our last their binding to DNA. In fact, not only can Omomyc sequester publication in Science Translational Medicine,1 we pre- CONTACT Laura Soucek lsoucek@vhio.net Vall d’Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d’Hebron, Barcelona, Spain © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. e1618178-2 M.-E. BEAULIEU AND L. SOUCEK MYC in dimers unable to recognize the E-box, it can also compete heterodimers, incapable of DNA binding, as well as Omomyc/ for MYC/MAX DNA binding in the form of Om Omomyc homodimers and Omomyc/MAX heterodimers, dis- omyc/Omomyc homodimers or Omomyc/MAX heterodimers.4 playing instead DNA binding ability. All these dimers putatively Omomyc was initially used in vivo in its transgenic form to contribute to MYC displacement from ~98% of its genomic establish for the first time the therapeutic potential of MYC locations. The displacement of MYC from its target promoters inhibition to stop tumor progression, and even led to tumor results in a marked transcriptional reprogramming of cancer eradication, while also providing validation of its safety in multiple cells, especially evident as reversion of the expression of MYC- mouse models of cancer, independently of their tissue of origin or related gene signatures. driving oncogenic lesions.5–8 Despite this undisputable therapeu- Our results in vitro prompted us to assess the Omomyc tic opportunity, though, Omomyc was deemed too bulky and unfit mini-protein’s therapeutic utility in a mouse model of to ever become a drug.9 KRas-driven Non-Small-Cell lung cancer (NSCLC). Our And this is where our last publication is really proving this first attempt was through intranasal administration of the assumption wrong. Cell-penetrating peptides (CPPs), also polypeptide, three times per week, at a dose of 2.37 mg/ known as protein transduction domains, have the ability to kg. A 4-week treatment prevented tumor progression and allow intracellular delivery of multiple cargos,10 and have caused regression to a lower tumor grade, as recently received considerable attention because of their high a consequence of both reduced proliferation and transduction efficiency and low cytotoxicity. In Beaulieu et al., increased cell death (Figure 1). Following Omomyc treat- 2019,1 making use of a purified, recombinantly produced ment, we also observed recruitment of intratumoral Omomyc polypeptide, we demonstrated for the first time that T cells, in line with the observed transcriptional repro- Omomyc’s basic region is a CPP itself. Treating several cancer gramming of cytokines and chemokines gene sets. cell lines with increasing concentrations of fluorescently labeled Similar results were also obtained with intravenously admi- Omomyc, we were able to observe internalization of the protein nistered Omomyc mini-protein to mice carrying xenografts of and partial localization in the nuclei at concentrations as low as human NSCLC H1975 cells, which are EGFR (epidermal 0.3 μM, causing growth arrest with an IC50 in the low micro- growth factor receptor), PI3K and P53 (tumor protein TP53) molar range. We also confirmed that the mini-protein acted as mutant, in addition to being resistant to erlotinib. Also in this its transgenic counterpart, being able to form Omomyc/MYC case, Omomyc treatment significantly reduced tumor Figure 1. Proof of concept of the pharmacological application of the Omomyc mini-protein as a therapeutic for the treatment of Non-Small-Cell Lung Cancer (NSCLC). The Omomyc mini-protein was administered intranasally (on the left) in a mouse model of KRAS-driven NSCLC and intravenously (on the right) in a xenograft model of human NSCLC H1975 cells, where it was either used alone or in combination with paclitaxel (PTX), considered in this case as standard of care (SOC). MOLECULAR & CELLULAR ONCOLOGY e1618178-3 progression. Moreover, when given in combination with Pozo E, Fiore C, et al. Intrinsic cell-penetrating activity propels paclitaxel (PTX), Omomyc had a higher therapeutic impact, Omomyc from proof of concept to viable anti-MYC therapy. Sci Transl Med. 2019;11(484). significantly extending the survival of the animals. (Figure 1) 2. Wasylishen AR, Penn LZ. Myc: the beauty and the beast. Genes Overall, our results provide the first evidence and preclinical Cancer. 2010;1(6):532–541. doi:10.1177/1947601910378024. validation of the Omomyc mini-protein as a specific pharmaco- 3. Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc logical MYC inhibitor and excellent candidate for clinical devel- and their clinical applicability. Front Cell Dev Biol. 2017;5:10. opment. The molecule is predicted to reach clinical trials in 2020. doi:10.3389/fcell.2017.00010. Importantly, our paper1 also provides the proof of concept 4. Soucek, L., Jucker R, Panacchia L, Ricordy R, Tatò F, Nasi S. for the use of therapeutic polypeptides to inhibit a well-known Omomyc, A potential Myc dominant negative, enhances difficult-to-target protein such as MYC, suggesting that Myc-induced apoptosis. Cancer Res. 2002;62(12):3507–3510. a similar approach might be extended to other challenging 5. Annibali, D., et al. Myc inhibition is effective against glioma and targets within cancer cells. reveals a role for Myc in proficient mitosis. Nat Commun. 2014;5:4632. doi:10.1038/ncomms5972. Conflict of interest 6. Sodir, N.M., Swigart LB, Karnezis AN, Hanahan D, Evan GI, Soucek L. Endogenous Myc maintains the tumor MEB and LS are both founders and shareholders of Peptomyc S.L. microenvironment. Genes Dev. 2011;25(9):907–916. doi:10.1101/ gad.2038411. Funding 7. Soucek L, Nasi S, Evan GI. Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ. 2004;11 This work was supported by the European Research Council [617473]; (9):1038–1045. doi:10.1038/sj.cdd.4401443. Instituto de Salud Carlos III [PI13/01705]; BBVA Foundation [67_2015]; 8. Soucek, L., Whitfield JR, Sodir NM, Massó-Vallés D, Worlwide Cancer Research [13-1182]. Serrano E, Karnezis AN, Swigart LB, Evan G. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 2013;27(5):504–513. doi:10.1101/ ORCID gad.205542.112. Marie-Eve Beaulieu http://orcid.org/0000-0001-5224-8436 9. Montagne, M., Beaudoin N, Fortin D, Lavoie CL, Klinck R, Laura Soucek http://orcid.org/0000-0002-4750-7971 Lavigne P. The Max b-HLH-LZ can transduce into cells and inhibit c-Myc transcriptional activities. PLoS One. 2012;7(2): e32172. doi:10.1371/journal.pone.0032172. References 10. Jauset T, Beaulieu ME. Bioactive cell penetrating peptides and 1. Beaulieu ME, Jauset T, Massó-Vallés D, Martínez-Martín S, Rahl proteins in cancer: a bright future ahead. Curr Opin P, Maltais L, Zacarias-Fluck MF, Casacuberta-Serra S, Serrano del Pharmacol. 2019;47:133–140. doi:10.1016/j.coph.2019.03.014.