EntreChem's mithralog EC-8042 targets sarcoma cancer stem cells by inhibiting SP1 transcription factor

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

Collectively, these data suggest that EC-8042 could constitute an effective anti-pluripotency treatment against both TICs and CSC subpopulations in sarcoma, a class of tumor that could benefit from senescence induction therapy.