Development of CHY-1 as a new drug candidate for the treatment of different types of breast cancer

Abstract

Breast cancer is considered the most common cancer type among women in Brazil and worldwide, not considering skin melanoma and it is estimated that 57,960 new cases of breast cancer will be diagnosed only in Brazil in 2016. Tumor heterogeneity of breast carcinomas is a great challenge to be faced, since tumors with the same characteristics may have different outcomes in relation to prognostic factors and responses to the available treatments. Thus, there is an urgent necessity for further research to develop new therapies that can significantly increase the chance of cure for patients who do not benefit from the currently available treatments. The CTP enzyme: phosphoethanolamine citidililtransferase (Pcyt-2), which uses as a substrate phosphoethanolamine is a key regulator in the Kennedy pathway for the production of membrane phospholipids. Inhibition of Pcyt-2 directly involves reducing glicerofosfolipídio zwitterionic phosphatidylethanolamine (PE). This phospholipid is one of the most abundant in eukaryotic cells and hence reducing its production could directly affect cell division, apoptosis, autophagy, especially in tumor cells. In a previous study, we confirmed that Pcyt-2 is a therapeutic target in lung cancer cells and identified a new lead compound, or prototype for the rational development of inhibitors Pcyt-2 enzyme: the CHY-1. This compound was used as a template for the rational development based on SBDD structure (structure-based drug design) of new potential inhibitors of Pcyt-2 enzyme. The CHY-1 compound is capable of reducing the intracellular levels of PE, reducing the autophagic flow in H460 and A549 cells. Interestingly, CHY-1 has an extensive in vivo therapeutic range, demonstrating no signs of toxicity in mice. Thus, the present project aims to study the inhibitory effect of CHY-1 on autophagy, determining its mechanism, besides analyzing in vitro and in vivo the effects of this new drug candidate in combination with therapeutic approaches already standardized for different types of breast cancer. This objective is based on recent studies that have investigated the association of chloroquine or hydroxychloroquine, two known inhibitors of autophagy with established treatments in an attempt to increase their effectiveness. Still, it will be evaluated whether the combination therapy in vivo and in vitro of CHY-1 with doxorubicin, cisplatina, tamoxifen and trastuzumab (analyzis will be performed only in vitro) has therapeutic benefits with fewer adverse effects.