- Triple Negative Breast Cancer (TNBC) at the molecular level shows alterations on receptor tyrosine kinases (RTKs), downstream signaling pathways involved in the regulation of proliferation and survival, and DNA repair machinery.
- EC-70124, a kinase inhibitor being developed at EntreChem SL, shows a multi-mode of action on TNBC by inhibiting several relevant signaling pathways and DNA damage repair.
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, has been presented in a poster in the 50th annual meeting of the American Society for clinical Oncology (ASCO 2014) held on May 30th – June 3rd 2014 in Chicago (USA).
The research, directed by Dr. Alberto Ocaña, Director of the Translational Cancer Research Unit, Albacete University Hospital, and participation from Dr. Atanasio Pandiella from the Translation Oncopharmacology Unit at CIC (Salamanca, Spain) 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 is active against a panel of TNBC cells in the submicromolar range and also in xenografted mice. EC-70124 inhibited relevant pathways in TNBC including the PI3K/mTOR pathway. In addition, it induced DNA damage and cell cycle analyses showed an arrest at the G2/M phase; that was confirmed by the biochemical evaluation of cell cycle mediators. Gene expression analyses showed different cellular functions induced by EC-70124, among them, up regulation of DNA repair genes, further confirmed by RT-PCR. Studies in combination with standard of care showed synergy with chemotherapeutic agents that act on DNA raising the possibility to explore these combinations in the clinical setting.
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.
The inhibitor EC-70124, is currently undergoing advanced preclinical development by EntreChem SL. EC-70124 is a hybrid natural product obtained from genetically modified bacteria by combinatorial biosynthesis.
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:
ASCO 50th meeting: abstracts.asco.org/144/AbstView_144_131160.html
CHUA: www.chospab.es/investigacion/oncologia_traslacional/intro.htm
CIC: www.cicancer.org
EntreChem SL: www.entrechem.com
