TR4: Inhibitor of notch activation.

Abstract

e13509 Background: We report on the development of a new class of therapeutic proteins that interfere with intracellular targets in both cancer cells and cancer stem cells (CSC). Methods: We used a delivery platform based on drosophila transcription factor antennapedia (ANTP) which allows for intracellular and intranuclear delivery as well as enabling the transport of agents across the blood-brain barrier. The following example exemplifies this approach: we have engineered a fusion protein, consisting of antennapedia (ANTP) and the truncated version of mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits the notch transactivation complex. This fusion protein, (ANTP/DN‐MAML) or TR4, has been tested for its ability to target tumor cells in vitro and in vivo. Results: TR4 has been: shown that it has a killing effect at clinically meaningful IC50; shown that it acts specifically on the notch pathway; and shown to be stable when stored and freeze/thawed. Conclusions: The results described here demonstrate the features of this approach with the principal benefit being the delivery of therapies with improved tissue and cellular penetration which may lead to improved efficacy of existing therapies and open up new treatment pathways.