Generating mRNA-HNF4a-Lipid nanoparticles for curing pancreatic cancer-associated cachexia (CAC) in identified patients at risk

Opis projektu

Leczenie kacheksji związanej z chorobą nowotworową

Wielu pacjentów onkologicznych cierpi na kacheksję nowotworową – wyniszczenie, które prowadzi do utraty wagi, zaniku mięśni i pogorszenia samopoczucia. Chociaż nie istnieją ani wiarygodne biomarkery, ani metody leczenia kacheksji, najnowsze dowody wskazują, że przed jej wystąpieniem w wątrobie pojawiają się pewne zmiany. Zmiany te są związane z infiltracją przez komórki układu odpornościowego i wyczerpaniem hepatocytowego czynnika jądrowego 4 alfa (HNF4a). Udowodniono w modelach mysich, że przywrócenie właściwego poziomu HNF4a łagodzi kacheksję, co sugeruje, że czynnik ten ma potencjał jako element strategii leczenia. Finansowany przez Europejską Radę ds. Badań Naukowych projekt CACure ma na celu opracowanie specyficznych dla wątroby metod dostarczania mRNA HNF4a i przeciwdziałanie kacheksji u pacjentów z rakiem trzustki.

Cel

"Cancer-associated cachexia (CAC) is a multifactorial syndrome causing significant morbidity and mortality in cancer patients and indicates a poor prognosis. Nearly 80% of cancer patients experience CAC, which directly accounts for almost 20% of all cancer deaths, mainly in patients with pancreatic adenocarcinoma (PDAC). Clinically, CAC manifests as weight loss and wasting of skeletal muscle mass. Thus, CAC patients experience reduced physical, emotional, and social well-being, leading to increased use of healthcare resources. The massive phenotypic manifestations point to a significant imbalance in the systemic metabolism of CAC patients. Unlike starvation, CAC cannot be reversed by standard nutritional interventions, and currently, there are no biomarkers for identifying patients at risk for CAC and no effective therapeutic modalities.
With our ERC (#818943), we identified changes in liver metabolism during extra hepatic carcinogenesis. We now demonstrate that these metabolic changes occur early, precede CAC, and can be diagnosed by routine liver biochemical profile. We generated a biochemical liver score that can identify PDAC patients at risk for CAC, irrespective of disease stage at diagnosis. Furthermore, we find that these metabolic changes in the liver are mediated by early infiltrating immune cells that lead to HNF4a depletion in hepatocytes independent of liver metastasis. Importantly, we find that re-expressing HNF4a with Adeno Associated Virus (AAV8) preserves liver metabolism in PDAC mouse models and alleviates CAC. We hence hypothesize that generating liver-specific mRNA of HNF4a will be highly therapeutically beneficial for PDAC patients identified by our liver score to be at risk for CAC. In this PoC we will generate and test the efficiency of novel HNF4a-mRNA-LNPs in preventing or alleviating CAC in PDAC mouse models. When successful, our optimized construct will undoubtedly serve identified PDAC and other cancer patients at risk for CAC.

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