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      Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

      review-article
      1 , 1 , 2 , 3 , 4 , *
      Cells
      MDPI
      omomyc, Myc, cancer, Myc inhibition, mouse models, peptides, anticancer drugs, new therapeutics

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          Abstract

          First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein—following the surprising discovery of its cell-penetrating capacity—constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.

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          Most cited references71

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          Myc's broad reach.

          The role of the myc gene family in the biology of normal and cancer cells has been intensively studied since the early 1980s. myc genes, responding to diverse external and internal signals, express transcription factors (c-, N-, and L-Myc) that heterodimerize with Max, bind DNA, and modulate expression of a specific set of target genes. Over the last few years, expression profiling, genomic binding studies, and genetic analyses in mammals and Drosophila have led to an expanded view of Myc function. This review is focused on two major aspects of Myc: the nature of the genes and pathways that are targeted by Myc, and the role of Myc in stem cell and cancer biology.
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            Drugging the 'undruggable' cancer targets

            In this Viewpoint article, we asked four scientists working to target important, but so-called 'undruggable', proteins in cancer for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of cancer research.
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              Modelling Myc inhibition as a cancer therapy.

              Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                04 April 2020
                April 2020
                : 9
                : 4
                : 883
                Affiliations
                [1 ]Peptomyc S.L., Edifici Cellex, 08035 Barcelona, Spain; dmasso@ 123456vhio.net
                [2 ]Vall d’Hebron Institute of Oncology (VHIO), Edifici Cellex, 08035 Barcelona, Spain
                [3 ]Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
                [4 ]Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
                Author notes
                [* ]Correspondence: lsoucek@ 123456vhio.net
                Author information
                https://orcid.org/0000-0003-4231-0456
                https://orcid.org/0000-0002-4750-7971
                Article
                cells-09-00883
                10.3390/cells9040883
                7226798
                32260326
                805ec41c-96a0-4334-952f-f4b92157245a
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 March 2020
                : 02 April 2020
                Categories
                Review

                omomyc,myc,cancer,myc inhibition,mouse models,peptides,anticancer drugs,new therapeutics

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