ONCOPHAGY · Novel Atg4B-inhibitors and dual [Atg4B-carbonic anhydrase] inhibitors for interfering with cytoprotective mechanisms of cancer cells in the acidic tumor micro-environment.

Novel Atg4B-inhibitors and dual [Atg4B-carbonic anhydrase]inhibitors for interfering with cytoprotective mechanisms of cancercells in the acidic tumor micro-environment.

Cancer cells are remarkably capable of surviving the harsh conditions present in tumors. In this framework, two metabolic adaptations of cancer cells have received significant attention: (1) the presence of chronic autophagy and (2) the strongly increased production of carbonic anhydrases (CAs). Autophagy is a process with which cells recycle old proteins and other life-sustaining building blocks. Autophagy allows them to limit the exchange of materials with their environment and this confers a protective effect, for example against chemotherapy and other cancer drugs. CAs are enzymes that are directly involved in maintaining a neutral pH inside the cells. They protect cancer cells against the tumor microenvironment, which is typically acidic. The project wants to block these protective processes in cancer cells and, in this way, aims at increasing cellular stress and making cancer cells more sensitive to therapy. Two strategies are followed. 1) Designing,making and testing molecules that block autophagy in cancer cells. These molecules are designed to disrupt the activity of a key player in autophagy: the protein Atg4B. 2) Design, make and test hybrid molecules, consisting of the Atg4B targeting moiety linked to a CA targeting moiety. The combined blocking of autophagy and CAs can be expected to be particularly effective at making cancer cells vulnerable. In the project, the newly prepared molecules are first extensively tested on cancer cells and normal cells. Molecules that combine the highest potency against cancer cells and a lack of toxicity against normal cells, are subsequently investigated in a battery of in vitro tests to predict behaviour in a living organism (e.g., stability in blood, resistance against liver metabolism). Only after maximal in vitro characterization, the single most promising molecule is allowed for testing in tumour-bearing mice. Cancer is the most common cause of death and morbidity in Europe, after cardiovascular diseases. In spite of continuous advance in the treatment of the disease, challenges to make cancer a 100% curable disease remain immense. The societal relevance of this project therefore is primarily related to the fact that it contributes to improvement of cancer therapy. In addition, autophagy and CAs are also emerging pharmacological targets in other areas (neurodegeneration, cardiovascular disease). The scientific innovativity of the project can be demonstrated using the following characteristics: 1) It delivers novel, specific autophagy inhibitors that target Atg4B. The relevance of these compounds is clear when taking into account both the currently unmet demand for reliable, specific autophagy inhibitors and the status of Atg4B as a daunting target. 2) To the best of our knowledge, no reports exist on the combined targeting of autophagy and CAs as an anti-tumor strategy. 3) The in vivo study allows to determine the translational potential of the compounds in the framework of cancer therapy and these data will directly support the economic valorization strategy of the work.

Data: CORDIS, © European Union