Grant for research towards a treatment for paragangliomas

Deen, Peter

Dr. Henri Timmers (Dept. of Internal Medicine) and Prof. Peter Deen (Dept. of Physiology, photo left) obtained a grant of nearly 750.000 Euro from the paradifference foundation to develop a treatment for paraganglioma’s caused by mutations in the mitochondrial succinate dehydrogenase (SDH) B subunit.

Pheochromocytomas and paragangliomas (PGLs) are rare tumors of parasympathetic and sympathetic paraganglia. Besides being tumors, sympathetic PGLs secrete excess catecholamines, giving severe headache, panic attacks, arrhythmias and hypertension. Molecular analyses revealed the that mutations in 12 genes confer germline susceptibility for PGL development of which cluster 1 genes involve inactivating mutations in Krebs cycle proteins, such as the SDH subunits A-D. Most metastatic PGLs associate with SDHB germline mutation and predispose to malignancy in 37-97% of the cases, but an appropriate treatment for SDHB PGLs is lacking.

In an international consortium of 5 different groups, our goals are to generate and set up a proper adrenal cell and zebra fish model for SDHB PGLs using CRISPR technology and to use these models to study the aetiology of the disease and to screen/test potential therapeutics. As SDH tumors are also characterized by excessive production of the mitochondrial metabolite succinate and increased expression of its receptor, SUCNR1, we will analyse the biochemical and metabolic changes induced by SDH inactivation, test the potential therapeutic role of SUCNR1 inhibitors in PGLs, and set up a cellular system to screen for inhibitors for the SUCNR1. Identified blockers will be tested for their efficacy to attenuate the SDHB phenotype in our cell/fish models. Besides these fundamental studies, our center will also serve as a recruitment and treatment center in the context of the clinical trials involving patients with metastatic SDHB PPGL. At present, a PhD position is vacant.

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