Cancer-associated cachexia (CAC) is a multifactorial syndrome, a significant cause of morbidity and mortality in cancer patients, and an indicator of poor prognosis. Nearly 80% of cancer patients experience CAC, which accounts for almost 20% of all cancer deaths, mainly in patients with pancreatic adenocarcinoma (PDAC). Phenotypically, CAC is associated with several manifestations encompassing functional, metabolic, and immune disorders and aggravated toxicity complications following cancer therapy. Consequently, patients experience impaired quality of life, and reduced physical, emotional, and social well-being, leading to increased use of healthcare resources. Clinically, CAC is defined by a greater than 5% weight loss, a more than 2% weight loss in individuals whose body mass index (BMI) is below 20 kg/m2, or by depletion in skeletal muscle mass. Metabolically, CAC-related dysfunctions include adipose tissue wasting, muscle atrophy, and decreased appetite. The massive metabolic manifestations point to a significant imbalance in the systemic metabolism of CAC patients. Intriguingly, unlike starvation, standard nutritional interventions cannot reverse CAC, and no correlation has been demonstrated between dietary intake and body composition parameters. We have shown that metabolic changes that precede CAC occur early in the host's liver, can be diagnosed by routine liver biochemical profile, and can predict CAC onset in PDAC patients, independent of disease stage at diagnosis. Furthermore, we found that these metabolic changes in the liver are mediated by early infiltrating immune cells that lead to HNF4 depletion in hepatocytes independent of liver metastasis. Importantly, re-expressing HNF4a with Adeno Associated Virus (AAV8) preserves liver metabolism in a PDAC mouse model and alleviates CAC manifestations. Thus, we proposed that identifying and treating PDAC patients at risk for CAC with mRNA- HNF4 liver nanoparticles (LNPs) will prevent CAC and improve PDAC patients' outcomes.
To test our proposal, we pursued the following aims: (i) Generate an effective HNF4 -mRNA-LNPs vector that penetrates hepatocytes; (ii) Optimize the dosage and mode of delivery required to express HNF4 in livers in- vivo; (iii) Evaluate the therapeutic efficiency of HNF4-mRNA-LNPs to prevent or alleviate PDAC-CAC.
