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Grant

Consortium Grant

Deen 10 Mar 2017

Pheochromocytomas and paragangliomas (PPGLs) are highly heterogeneous neuroendocrine tumors, but usually do not metastasize and are therefore usually cured by surgical intervention. However, in PPGLs due to mutations of the succinate dehydrogenase subunit B (SDHB) gene up to 80% of affected patients develop metastatic disease for which there is currently no effective cure. Recently, Prof. Peter Deen (physiology) and Dr. Henri Timmers (internal medicine) obtained a 1.200.000 Euro consortium grant from the paradifference foundation. In this consortium, which they coordinate, they will, together with Profs Stunnenberg (mol. biol. RU), Hans Clevers (Hubrecht, Utrecht), Shane Ellis (M4I, Maastricht) and two addition clinical groups, employ human tumors to increase our understanding of the etiology of PPGL tumor formation using state-of-the art omics techniques and to develop human organoid model systems.  

Details: 

Pheochromocytomas and paragangliomas (PPGLs) are highly heterogeneous neuroendocrine tumors, but usually do not metastasize and are therefore usually cured by surgical intervention. However, in PPGLs due to mutations of the succinate dehydrogenase subunit B (SDHB) gene up to 80% of affected patients develop metastatic disease for which there is currently no effective cure. Available therapies are palliative and rarely result in complete remission. While it is well recognized that understanding the etiology of tumour formation and the availability of proper disease models to test/screen for drugs correcting the diseased phenotype are essentials to develop therapies, the present knowledge of pathways affected in SDHB-PPGLs is far from complete, as it is based on low-sensitivity techniques. Moreover, generation of proper disease models for SDHB-PPGLs has not been successful, as animals lacking the SDHB gene do not recapitulate PPGLs, and used PPGL cell models are mutated in other PPGL-causing genes, or it cannot be confirmed to properly mimic SDHB-PPGLs. As such, human model systems are desperately needed.

In this present proposal, three clinical PPGL expert groups team up with world-recognized experts groups to fill these gaps: using state-of-the-art techniques, that are >1000-fold more sensitive than previously used techniques, the quantitative transcriptome, epigenome and metabolome will be determined of the same SDHA/B/D and VHL PPGLs at cell-based resolution. The anticipated integrated data will (1) reveal detailed pathways that are characteristic for PPGLs of each molecular signature, (2) provide explanations why SDHB-PPGLs are more aggressive than PPGLs of other molecular signature, (3) provide a list of genes that will solve the issue to what extent a SDHB-cell/animal model system mimics the tumour, and, last but not least, (4) yield therapeutic targets and potential therapies deduced from information of the tumours themselves. In addition, starting from fresh PPGL tumour tissue provided by the three clinical PPGL groups, human SDHx-mutant organoids and cell models will be created, bio-banked, and made available for identifying drugs candidates for translation into clinical trials.


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