LXRα induced lipotoxicity for cancer treatment

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Solid tumors acquire significant changes in metabolic pathways during development due to their specific biosynthetic demands and their particular microenvironment. However, the development of cancer therapies that are based on the inhibition of biosynthetic pathways is often limited by the high plasticity and adaptability of metabolic networks, e.g. resulting in activation of compensatory pathways or in an increased exchange of metabolites between cancer cells and the tumor environment. Therefore, such therapies could not be translated into efficient clinical applications so far.Within the DFG research group FOR2314, we could recently show that enhanced liponeogenesis, triggered by a pharmacological activation of the Liver X receptor alpha (LXRα), represents a new therapeutic strategy for the treatment of liver carcinoma (HCC). A combination of LXRα mediated fatty acid synthesis and concomitant Raf suppression results in oxidative stress, induction of a critical endoplasmic reticulum stress response and subsequently in apoptosis of different murine and human liver cancer cells. Our mechanistic studies identified Raf-1 as an important regulator of lipid metabolism in liver tumors. We found that Raf-1 directly interacts with Stearoyl-CoA desaturase-1 (SCD1), the central enzyme for the conversion of saturated into mono-unsaturated fatty acids and thereby maintains SCD1 protein stability in HCC cells. Inhibition of Raf-1 by DFG-out Raf inhibitors diminished SCD1 protein abundance, leading to toxic accumulation of saturated fatty acids and metabolic stress in cancer cells under sustained lipogenesis. Treatment studies in genetically defined or steatohepatitis (NASH)-induced liver cancer mouse models and xenograft models of human HCC revealed that a combinatorial therapy, comprising an LXR agonist and a DFG-out Raf inhibitor efficiently suppress liver cancer development and prolong the survival of tumor bearing animals. Such a therapy was well tolerated by mice, even by animals that already suffer from a fatty liver disease.With this proposal, we aim to further investigate our lipotoxic therapy and the identified Raf-1-SCD1 protein complex. We want to understand how Raf-1 interacts with SCD1 and how this interaction maintains SCD1 protein stability. Furthermore, we want to determine the relevance of this protein complex in other tumor entities and evaluate the therapeutic response of these tumors to this lipotoxic therapy. To further improve the therapeutic effect of this lipotoxic therapy, we aim to identify mechanisms of therapy resistance upon long-term treatment. We will perform mRNA expression analyses and an in vivo RNA interference screen to identify potential resistance mechanisms. Finally, we plan to explore the role of the immune system in tumors treated with this lipotoxic therapy. We will analyse the recruitment of immune cells during treatment and determine their role in the treatment response with immunodeficient mice.