Targeting cytidine deaminase with an intracellular antibody-based degrader to overcome chemoresistance in cancers – NanoDegradRESIST

Despite the improvements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents continues to be a major problem in cancer therapies. Indeed, drug resistance is responsible for most relapses of cancer, one of the major causes of death of the disease. Therefore, it is essential to better understand these mechanisms of resistance to identify novel targets and define efficient therapeutic approaches to ultimately improve patient’s management. Intracellular antibody reagents, i.e. antibodies expressed inside the cells, are one appealing avenue to accelerate this process. The advantages of intracellular antibody-based reagents are that their high affinity and specificity can be exploited to modulate the function of intracellular targets that are hard-to-drug by conventional approaches (e.g. RNA/DNA- or small molecule-based methods). Deoxycytidine analogues (e.g. gemcitabine, cytarabine) are an important class of chemotherapeutic agents used in a variety of cancers, such as pancreatic and lung cancers or acute myeloid leukaemia. Nevertheless, resistance mechanisms limit their efficacy. Interestingly, cytidine deaminase (CDA) has been identified as a key regulator of resistance to these agents by promoting their deamination and inactivation. However, current inhibitors targeting CDA active site have a limited efficacy and/or off-target issues. Therefore, our project aims to develop an innovative therapeutic approach using a potent and specific intracellular antibody-based degrader targeting CDA. This molecule is expected to provide a therapeutic solution to overcome resistance to deoxycytidine analogue-based chemotherapies in cancers. This proposal will encompass the in vitro to in vivo validation steps, the exploration of potential mechanisms of acquired resistance that may arise from this approach and the delivery of this intracellular therapeutic protein in tumours. The results from this project may be applied to other targets and/or other diseases.