Dual inhibition of energy-producing pathways in hepatocellular carcinoma models.

Abstract

Reprogramming of metabolic pathways is an essential hallmark of accelerated proliferation and growth of cancer cells. Emerging data proposes that fasting, as an adjuvant in cancer therapy, can improve treatment efficacy in various cancer types by exploiting and targeting their dysregulated metabolism, without affecting non-transformed cells. Hepatocellular carcinoma (HCC), the primary form of liver cancer, is characterized by high genetic heterogeneity, which increases the challenge to identify effective treatment strategies. Particularly, the prognosis for patients with late-stage HCC remains poor, due to the development of resistance against standard-of-care drugs. Previous studies have shown that fasting reinstates the sensitivity to Sorafenib in resistant HCC models by simultaneously tackling multiple growth pathways. Metabolic analyses demonstrated that Sorafenib non-canonically inhibits mitochondrial respiration, which forces malignant cells to perform a “Warburg shift” in order to survive. This escape to glycolysis is curtailed by the limiting access of glucose in combination therapy.

Date of Award	2022
Original language	English
Awarding Institution	University of Graz
Supervisor	Andreas Prokesch (Supervisor) & Jelena Krstic (Co-supervisor)