Development of a Pancreatic Cancer drug-Nanocarrier system selectively targeting tumour cells and tumour stroma to overcome treatment failure
PaCaNano hypothesizes that therapeutic failure in pancreatic cancer (PC) can be overcome via a novel nanoparticle (NP) technology that allows targeting both cancer and stroma cells. To deliver proof-of-concept, we have selected gemcitabine phosphate (GemP) nanoparticles, recently developed by project partners KIT and UMG. These NPs have a very high gemcitabine load (80% by mass) and have already shown preclinical promise in PC. PaCaNano aims to further optimize these NPs by adding ‘tumor homing’ units:
1) a ‘diabody’, patented by partner UNIFI, that will guide GemP-NPs to PC cancer cells. 2) Alternatively, a UAMC1110 derivative will be used that offers specificity for FAP+ cancer-associated fibroblasts (CAFs). UAMC1110 was discovered by partner UANTWERP. It is the CAF-targeting unit of all ‘FAPI’ theranostics.
We will also add FAP-activatable, non-toxic chemotherapy prodrugs to the stroma-targeting NPs. For this, SN38, vedotin and daunorubicin have been selected. SN38 is the toxic, active metabolite of irinotecan which is also part of the FOLFIRINOX therapy in PC. Vedotin and daunorubicin are highly toxic chemotherapeutics, of which the potential could be exploited in PC via direct delivery to the tumor. PaCaNano will investigate all NPs first in vitro: in cells (cancer cells/CAFs), in PC-tissue and in patient-derived organoids. In vivo research will include biodistribution and efficacy studies in KPC and PC-PDX mice. In this framework, we will also investigate a 2-step strategy: FAP-targeting NPs are first used to ablate the dense tumor stroma. This will expose cancer cells, which will be targeted with the corresponding GemP-NPs in a second step. The ability to deliver highly cytotoxic drugs in high concentrations specifically to tumor/metastases is expected to minimize adverse effects and maximize therapeutic benefit, with a higher chance of curing PC patients. The NP platform is also very flexible and can be applied to other chemotherapeutics and cancer types.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.