Molecular targets for more efficient therapy of Cushing's syndrome

Würzburg. It helps against stress, but also causes stress: cortisol! On the one hand, the stress hormone fulfils important functions in the human metabolism. For example, it ensures that our body has enough energy under increased stress and inhibits inflammation. However, if it is taken in high doses over a long period of time or released uncontrollably via the adrenal glands, it throws the body into chaos: many people affected not only develop an overweight belly, a round face and a strong neck, but also high blood pressure, muscle weakness, diabetes and become more susceptible to infections. The sum of these symptoms is also known as Cushing's syndrome.

Tumour in the pituitary gland causes increased cortisol levels and Cushing's syndrome
Cushing's syndrome is triggered in a good 70 percent of all cases by benign tumours of the pituitary gland, a pea-sized gland below the brain. The tumour causes the pituitary gland to produce the hormone adrenocorticotropin (ACTH) unchecked, which triggers the adrenal glands to release cortisol. Despite surgical treatment - with removal of the mass responsible for the hormonal excess - many sufferers are subsequently not permanently cured and require drug treatment. However, the drugs are often not sufficiently effective and frequently have numerous side effects. What happens in tumours that release ACTH without restraint was unknown for a long time, which slowed down the development of new therapies. A research team from the Department of Endocrinology at the University Hospital Würzburg (UKW) wants to change this. Deciphering the causes of endogenous Cushing's syndrome in both clinical and scientific approaches has been the research focus of the team led by Prof Dr Martin Fassnacht for more than ten years.

Mutation in genes USP8 and USP48 responsible for half of all Cushing's disease tumours
„Together with colleagues from Munich and Japan, we were the first to identify a mutation in the USP8 and USP48 genes;nchen and Japan, we were the first to show in a study published in the journal Nature Genetics (1) that mutations in the deubiquitinase gene USP8 were responsible for Cushing's syndrome in around a third of tumours,
reports Dr Silviu Sbiera. Silviu Sbiera, head of the Würzburg Endocrinological Research Laboratory. „In 2019, we published another disease-causing mutation in the deubiquitinase gene USP48 in the journal NeuroOncology (2). This means that somatic mutations in the deubiquitinase system are responsible for half of all Cushing's disease tumours, which makes this system extremely important for this rare disease.“ Humans have around 100 different deubiquitinases. The enzymes can regulate the stability of proteins. 

DFG funds research project with 580.450 euros 
The results so far have convinced the German Research Foundation DFG, which has already funded numerous projects on the adrenal gland individually and as part of the Transregio 205 Collaborative Research Centre, so that it is now supporting further investigations to understand the processes in ACTH-producing pituitary tumours with an individual grant of 580,450 euros. The research project is led by Silviu Sbiera and Martin Fassnacht as well as Nikita Popov, Professor of Ubiquitin Signalling in Cancer in the Department of Clinical Tumour Biology at the University Hospital of Tübingen. Also involved are the Core Unit Bioinformatics at the Comprehensive Cancer Center Mainfranken, the Neurosurgeries at the University Hospitals Erlangen, Hamburg-Eppendorf and Tübingen, the Genomic Core Facility and the Proteome Center at the University Hospital Tübingen and the Department of Cell and Chemical Biology at the Leiden University Medical Centre in the Netherlands.

The new research project is divided into four work packages: 1) Production of human cell lines with different genetic backgrounds and use as 2D and 3D models. 2) In-depth characterisation of the influence of USP8 and USP48 mutations on signalling pathways in the cells. 3) In-depth analyses of the interaction between the immune system and Cushing's disease tumours. 4) Establishment of prognostic markers and potential therapeutic targets. 

More efficient therapies through better understanding of molecular pathogenesis
„We hope to better understand the molecular features induced by the mutations in the deubiquitinase genes in the majority of Cushing's disease cases. If we can describe their influence on the DNA repair level and the progression of tumours more precisely, it will probably also be possible to characterise mechanisms of antitumour immunity and immune escape mechanisms more comprehensively. In a second step, we aim to use our newly developed cell systems to identify molecular targets that can be addressed by future individualised therapies," says Silviu Sbiera, summarising the vision. And Martin Fassnacht adds: „We hope that our findings will contribute in the medium and long term to the development of more efficient drugs with fewer side effects for this and possibly also for other pituitary disorders.“

Press release of the University Hospital of Würzburg from 23 January 2023