Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancer types. It is virtually resistant to any sort of therapy, including the most recent immunotherapies. These tumors are characterized by a strong hypoxic, nutrient poor, and acidic tumor microenvironment (TME), in which cytotoxic CD8+ T cells are excluded or absent. In the context of tumor acidity, the role of bicarbonate transporters, key regulators of pH homeostasis, has mostly been neglected so far. Supported by the ERC consolidator grant ImmunoFit, we recently unveiled that the metabolic editing of the TME via inhibition of a specific bicarbonate transporter in cancer cells represent a novel robust therapeutic strategy to mitigate the acidity of the TME, increase the fitness of CD8+ T cells, and render more effective the current immunotherapeutic regimens in pancreatic cancer. To progress on the path from ground-breaking research towards innovation we now propose to de-risk the target by delivering early lead compounds (i.e. blockers) with proven therapeutic efficacy and synergism with immunotherapies in several preclinical tumor models, to be valorized for add-on cancer therapy through follow-up R&D collaborations and/or licensing agreements with Pharmaceutical & Biotech companies. This will lead to the commercialization of our sciences and broad societal impact with the deliverable of a brand-new therapeutic approach and combination regimens which are urgently required to tackle tumor resistance or refractoriness vis-à-vis immunotherapies.
Fields of science
- HORIZON.1.1 - European Research Council (ERC) Main Programme