- The fusion protein EWS-FLI1 is a constitutively activated transcription factor responsible for the oncogenic phenotype of Ewing sarcoma (EWS). Mithramycin is a potent inhibitor of EWS-FLI1, but its toxicity makes it desirable to identify more potent and/or a less toxic analogs to inhibit EWS-FLI1 at clinically achievable concentrations.
- EntreChem’s mithralog EC-8042 is substantially less toxic than mithramycin in multiple species and maintains suppression of EWS-FLI1 at similar concentrations in vitro. EC-8042 is active in xenograft models of EWS at non-toxic doses with a promising therapeutic window potentially achievable in future clinical trials.
The results of a collaborative research from EntreChem SL (Oviedo, Spain), the National Cancer Institute (NCI, Bethesda, MD, USA), Vanderbilt University (Nashville, TN, USA) and Van Andel Institute (Grand Rapids, MI, USA) focused on a new strategy for treating Ewing Sarcoma (EWS), have been published in the journal Clinical Cancer Research.
The research, directed by Patrick Grohar, Ph.D. M.D., formerly at the Vanderbilt School of Medicine and now at the Center for Cancer and Cell Biology at Van Andel Research Institute, and with contributions, among others, from Lee J. Helman, MD (Scientific Director NCI), Dr. Min He (DTP program, NCI) and Dr. Malcolm A. Smith (Clinical Investigation Branch, NCI) screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma cell lines.
Both mithramycin and EC-8042 suppress the activity of EWS-FLI1, which belongs to a class of molecules called transcription factors that play key roles in genes regulation. In Ewing sarcoma, EWS-FLI1 switches certain genes “on” or “off” incorrectly, leading to uncontrolled cellular proliferation and, ultimately, tumors. Although transcription factors are difficult to target for drug treatment because of their structure, this study shows they offer significant opportunities for developing more precise therapies that perform better and have fewer side effects.
The study compared the IC50 to the maximum tolerated dose established in mice to determine the relationship between efficacy and toxicity, and confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. EC-8042 is a less toxic mithralog, and achieves suppression of EWS-FLI1 comparable to that of mithramycin.
In addition, the study established an improved therapeutic window to model the effects on cellular proliferation in EWS cells relative to HepG2 control cells. EC-8042 is less toxic to immortalized hepatocytes at concentrations that suppress EWS-FLI1 in EWS cells without causing DNA damage, while mithramycin suppressed EWS-FLI1 at relatively high concentrations that produced marked DNA damage.
An orthotopic xenograft model of EWS was used to evaluate in vivo activity, and comparing iv to ip routes of administration. EC-8042 showed excellent activity in the orthotopic model, and the activity was independent of the route of administration. Intravenous treatment produced a marked suppression of tumor growth that extended the survival of the EC8042-treated mice. Intraperitoneal treatment caused regressions in all treated mice and extended survival. Post-mortem tumor tissue analysis showed clear suppression of EWS-FLI1 activity on day 3 of treatment, as revealed by analysis of NR0B1 expression.
For full details see: Osgood et al. Identification of mithramycin analogs with improved targeting of the EWS-FLI1 transcription factor, Clinical Cancer Res 2016, 0000.
Collectively, these results provide a basis for the continued development of EC-8042 as an EWS-FLI1 inhibitor for the clinic, and highlights the therapeutic opportunities offered by targeting transcription factors.
Clinical Cancer Research publishes innovative clinical and translational cancer research studies that bridge the laboratory and the clinic.
The inhibitor EC-8042 is currently undergoing preclinical development by EntreChem SL (therefore not yet available for human assays). EC-8042 is a hybrid natural product obtained from genetically modified bacteria by combinatorial biosynthesis.
EntreChem SL is a spin off company created from research developed in the University of Oviedo, and its shareholders include, local Family Offices. Private financing is complemented by regional, national and european public programs.
More information:
Dr. Patrick Grohar: patrick.grohar@vai.org, +1 616 234 500
Dr. Francisco Morís: fmv@entrechem.com, +34 985 259 021
and also:
Van Andel Research Institute, VARI: http://groharlab.vai.org
EntreChem SL: www.entrechem.com
