Sp1

Sarcoma models derived from human mesenchymal stromal/stem cells (hMSCs) are used to understand better the initiation of sarcomagenesis, not amenable to analysis in patient samples or cell lines. This study shows that the signaling mediated by SP1 is altered in transformed hMSCs able to initiate sarcomas in vivo. The inhibition of SP1-mediated transcription by mithralog EC-8042 is an efficient strategy to target sarcoma tumor initiating cells (TICs) in vitro and to inhibit tumor formation in vivo. In addition, EC-8042 is not recognized as a substrate by ABC efflux pumps involved in drug resistance and may act as an anti-pluripotency therapy able to eliminate TICs and cancer stem cell (CSC) subpopulations in sarcomas. The results of a collaborative research from EntreChem SL and the Hospital Universitario Central de Asturias, HUCA (Oviedo, Spain), focused on a new strategy for treating sarcomas, especially targeting the tumor initiating cells (TICs) and their derived cancer stem cells (CSC) subpopulations, have been published in the journal Oncotarget. The research, directed by René Rodríguez, Ph.D., at the HUCA, and with contributions, among others, from Aurora Astudillo, Ph.D. M.D. (Pathology Department, HUCA), used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma.SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithralog that inhibits altered transcription in tumors and with excellent safety profile. EC-8042 treatment efficiently inhibited the growth of TICs cultures and upregulated the expression of the adipogenic factor CEBPα. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and a senescent-like state. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. For full details see: Tornín et al. Inhibition of sp1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma, Oncotarget 2016, doi: 10.18632/oncotarget.8817 Oncotarget ia a multidisciplinary traditional journal with free-access. Oncotarget mission is to make scientific results rapidly and widely available. The journal helps all researchers contribute to the progress of science. 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, the original co-founders and local family offices, especially Alimerka. Private financing is complemented by regional, national and european public programs like NEOTEC program (MICINN), Genome Spain Foundation, FICYT, IDEPA, SRP and 7FP from the European Union. More information: Dr. René Rodríguez: renerg@ficyt.es, +34 985 107 937 Dr. Francisco Morís: fmv@entrechem.com, +34 985 259 021 and also: IUOPA at HUCA: www.unioviedo.es/Oncologiatro.htm EntreChem SL: www.entrechem.com