Specific immunotherapeutic targeting of malignant hepatocytes enabled by transient and controlled ATP depletion

• Applicant: Professor Dr. Albrecht Wendel, since 12/2006
• Subject Area: Pharmacology
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 30738365

Hepatocellular carcinoma represents a prime cancer worldwide with an overall poor prognosis. The isolated hepatic perfusion (IHP) has been developed for exposing the liver to high doses of e.g. the cytostatic melphalan either alone or in combination with tumor necrosis factor alpha (TNF). However, the initiation of cell death in normal hepatocytes is a major limitation of this approach. It is proposed here to introduce selectivity into liver tumor therapy by exploiting the energy dependence of hepatocyte apoptosis. Previous own work showed that a high fructose load depletes metabolically healthy hepatocytes of ATP with the consequence that apoptosis induced either by TNF or melphalan is blocked. In contrast, dedifferentiated hepatic cancer cells are lacking this fructose metabolizing capability, i.e. their intracellular ATP is not depleted. In pre-clinical in-vivo experiments we showed that under controlled ATP-depleting conditions mouse livers but not hepatic tumor cell lines are fully protected against liver failure induced by melphalan, or by TNF. The overall goal of this study is to elaborate a treatment schedule allowing the selective elimination of malignant hepatocytes by melphalan- and TNF-induced apoptosis, while healthy hepatocytes are protected by controlled, transient fructose-induced hepatic ATP depletion.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Gerald Künstle, until 12/2006