463P - Development of Cancer Stem Cells Therapeutics

Abstract

ABSTRACT Disclosure A.A. Epenetos: Receive directors fees from Trojantec ltd. All other authors have declared no conflicts of interest. Cancer Stem Cells, (CSCs), are responsible for the initiation, metastasis and recurrence of a variety of cancers and may be a key reason for the failure of current therapies. Cancer Stem cells operate through similar signaling pathways as normal stem cells such as Notch, Hedgehog,Wnt and others. Notch signaling is abnormal in many, if not all cancers as shown in cancer stem cell development. Furthermore, it may be that some cancers are ‘addicted’ to Notch signaling. This presents opportunities for tumour-specific intervention. As all the signaling cascades converge on the Notch transcriptional complex (NTC) in the nucleus, we have developed a novel synthetic protein acting as a Notch inhibitor operating at nuclear level. This protein is based on the cell penetrating protein (CPP) antennapedia (Antp) produced together with a dominant-negative truncated mastermind-like protein (DN-MAML) called TR4. TR4 has been shown in vitro and in vivo to have anti-Notch and anti-cancer activity with similar potency to many of the gamma-secretase inhibitors or monoclonal antibodies being developed by others against this pathway, but it is completely specific for the NTC. In summary, a specific Notch inhibitor has shown anticancer activity and could now be considered for clinical development.