|EntreChem's orally active EC-70124 reverts tumorigenic
and stem cell properties in prostate cancer
March 10th, 2016 - Oviedo (Spain)
||Cancer stem cells (CSCs) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs.
||EC-70124, is a potent dual inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs, which exhibited over-activation of these transcription factors.
The results of a collaborative research from EntreChem SL (Oviedo), and the Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR, Bellinzona, Switzerland), focused on searching new strategies against prostate cancer, the most common epithelial cancer and the third leading cause of cancer death in men in western countries, have been published in the journal Molecular Cancer Therapeutics.
The research, directed by Dr. Carlo Catapano (IOR), focuses on the frequently activated STAT3 and NF-kB transcription factors and their blocking by the multi-kinase inhibitor EC-70124 both in tumorigenic and cancer stem cells populations of prostate cancer cells. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice.
Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo.
EC-70124 in vivo, when dosed orally, significantly delayed tumor growth without signs of toxicity, and treatment with the drug reduced both pIkb and pSTAT3 levels in the tumors of treated mice, confirming the effect of the drug in the NF-κB and STAT3 pathways.
Collectively, these findings underscore the ability of EC-70124 to act as a dual inhibitor of STAT3 and NF-κB signaling in vitro and in vivo. This novel kinase inhibitor with its action on two key signaling pathways may represent the prototype of a new class of anticancer drugs with ability to interfere with CSCs in prostate tumors providing tools for innovative approaches for treatment of advanced prostate cancer.
For full details, see: Civenni G et al, EC-70124, a novel glycosylated indolocarbazole multi-kinase inhibitor, reverts tumorigenic and stem cell properties in prostate cancer by inhibiting STAT3 and NF-kB, Mol. Cancer. Ther. 2016; pii: molcanther.0791.2015.
EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer.