- EC-70124, a kinase inhibitor, shows in vitro and in vivo antiproliferative effects mediated by simultaneous inhibition of the PI3K/mTOR y JAK/STAT signaling pathways and also DNA damage induction, causing cell cycle arrest on G2/M. The combination with docetaxel is synergistic, both in vitro and in vivo, offering opportunities for combination therapy with drugs currently in clinical use.
- EC-8042, a low toxicity mithralog, shows greater in vitro antiproliferative activity in TNBC cell lines than in other types of breast cancer, and its action is characterized by cell cycle arrest in G2, coinciding with an increase of pCDK1 and Wee1, and it also triggers apoptosis mainly in a caspase-independent manner. The combination with docetaxel is synergistic, both in vitro and in vivo, offering opportunities for combined therapy.
The results of a collaborative research from EntreChem SL (Oviedo) and the Translational Cancer Research Unit at Albacete University Hospital, CHUA (Albacete, Spain) focused on searching new strategies for Triple Negative Breast Cancer, which accounts for approximately 15%-25% of all breast cancer cases, have published in two separate research papers in the journal Oncotarget.
The research on EC-70124, directed by Dr. Alberto Ocaña (CHUA) and participation from Dr. Atanasio Pandiella (CIC) focuses on receptor tyrosine kinases (RTKs) like EGFR, FGFR, PDGFR, downstream signaling pathways involved in the regulation of proliferation and survival, like PI3K/mTOR and alterations of the DNA repair machinery involving among others BRCA1 and BRCA2. It is of note that clinical studies evaluating drugs targeting single receptors have shown disappointing results suggesting that therapeutic strategies should be designed to inhibit a number of key oncogenic nodes, making this subset of breast cancer tumors a high medical need in search of polypharmacology solutions.
EC-70124 shows in vitro and in vivo antiproliferative effects mediated by simultaneous inhibition of the PI3K/mTOR and JAK/STAT signaling pathways and also DNA damage induction, causing cell cycle arrest on G2/M. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Studies in combination with standard of care showed synergy with chemotherapeutic agents that act on DNA (i.e. docetaxel) raising the possibility to explore these combinations in the clinical setting.
For full details, see: Cuenca-López MD et al, Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer. Oncotarget. 2015 Sep 29; 6(29):27923-37
The prognosis of TNBC patients is poor due to the limited therapeutic options and the lack of specific targeted agents. The multitargeted kinase inhibitor EC-70124 shows activity in RTKs and downstream routes as well as induce DNA damage in addition to the anti-proliferative effect. All this actions can now be achieved only by combination of different drugs, so EC-70124 represents an opportunity to explore a polypharmacology approach in Triple Negative Breast Cancer.
In the case of the mithralog EC-8042, the research, led by Dr Atanasio Pandiella (CIC) and with participation of Dr. Alberto Ocaña (CHUA), shows the lines of TNBC are more sensitive to the drug than others of breast cancer not from this subgroup, and has in vivo activity in mice implanted with human cells of TNBC. From a mechanistic point of view, EC-8042 causes cell cycle arrest in G2, coinciding with an increase of pCDK1 and Wee1, in addition to apoptosis, mainly by caspase-independent mechanisms.
It is noteworthy that EC-8042 synergizes in vitro with drugs commonly used for TNBC, and it boosts the effects of docetaxel in vivo. Collectively, these data show a promising antitumor effect and the strengthening of the action of standard of care drugs used in the therapy of TNBC, which together with the very favorable toxicity profile opens the possibility of clinical evaluation of EC-8042.
The complete results are found in: Pandiella A et al, Antitumoral activity of the mithralog EC-8042 in triple negative breast cancer linked to cell cycle arrest in G2. Oncotarget. 2015 Sep 30.
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.
EC-70124 and EC-8042 are hybrid natural products obtained by combinatorial biosynthesis from genetically modified bacteria, and are currently in advanced preclinical studies by EntreChem SL (not available yet for trials in humans).
EntreChem SL is a Spanish spin off from the University of Oviedo, and its shareholders include original co-founders and local family offices. Private financing is complemented by public funds from MINECO, Genome Spain Foundation (now FECYT), FICYT, IDEPA, SRP and the 7FP and H2020 from the European Union.
More information:
Dr. Alberto Ocaña: albertoo@sescam.jccm.es, +34 967 597 100, ext. 37087
Dr. Atanasio Pandiella: atanasio@usal.es, +34 923 294 815
Dr. Francisco Morís: fmv@entrechem.com, +34 985 259 021
and also:
CHUA: www.chospab.es/investigacion/oncologia_traslacional/intro.htm
CIC: www.cicancer.org
EntreChem SL: www.entrechem.com
