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New treatment method for liver cancer successfully tested in preclinical phase

A preclinical study at the University Hospital Tübingen shows promising effects in hepatocellular carcinoma (HCC) caused by non-alcoholic steatohepatitis (NASH)

At the University Hospital of Tübingen, the preclinical study by Dr. Daniel Dauch and Prof. Dr. Lars Zender, Medical Director of Medical Oncology and Pneumology, led to the extremely positive preclinical results. The research groups pursued a new therapeutic approach, which they themselves refer to as "induced lipotoxicity," aimed at overcoming treatment resistance in hepatocellular carcinoma. The new study with the original title “LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer" was published today in the renowned scientific journal "Nature Cancer".

The new approach involves therapeutic intervention in the lipid metabolism of tumor cells. Activation of the so-called LXRα protein leads to an increase in fatty acid synthesis. Initially, this can be tolerated by the tumor cell, because saturated fatty acids (also known as bad fatty acids in nutritional medicine) are continuously converted to unsaturated (good) fatty acids by the enzyme stearoyl-CoA desaturase-1 (SCD1).

However, if a second protein, the so-called Raf-1 kinase, is inhibited at the same time, saturated fatty acids accumulate in the tumor cell, which cannot be tolerated by the tumor cell and leads to cell death of the tumor cell. Of particular importance is the fact that the new therapeutic concept has a strong efficacy against liver cancer, which is caused by fatty liver disease (NASH). Clinical trials have shown that these so-called NASH-HCCs are difficult to control with currently available targeted therapies or immunotherapies.

With the promising preclinical data, Prof. Dr. Lars Zender looks to the future with hope: "Liver cancer is already a global problem, and the incidence will continue to rise due to fatty liver disease in the coming decades. Our new therapy procedure should be further developed within the framework up to clinical application and subsequently tested in a clinical trial."

Dr. Daniel Dauch emphasizes that Tübingen is the ideal location to develop the novel therapeutic procedure to clinical application: "Due to the strong environment with internationally competitive cancer research in the oncological excellence cluster iFIT and the designation of Tübingen as a site in the National Center for Tumor Diseases (NCT), optimal conditions exist for translational cancer research and testing of new therapeutic methods in the context of early clinical trials." 

Hepatocellular carcinoma (HCC) accounts for 85-90 percent of all cases of primary liver cancer and is one of the leading causes of cancer-related death worldwide (with more than 750,000 deaths per year). The incidence of hepatocellular carcinoma is expected to continue to rise due to steadily increasing rates of fatty liver disease. The data from the preclinical study are very encouraging and might in the future lead to a better treatment of liver cancer patients.

Image caption:

Treated liver tumor under the microscope. While the tumor cells (upper part of the picture) are strongly affected by the lipotoxic therapy (formation of characteristic lipid droplets and cell death), normal liver cells (lower part of the picture) are only barely affected by the therapy. © University Hospital Tübingen

Original publication title: Rudalska R et. al. LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nature Cancer (2021)

DOI: 10.1038/s43018-020-00168-3

The publication is available at the following URL: https://www.nature.com/articles/s43018-020-00168-3