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Impact des mutations SDH sur la réponse antitumorale et identification de nouveaux biomarqueurs

Abstract : Pheochromocytomas and paragangliomas (PPGL) are very rare neuroendocrine tumors (<2 cases/1,000,000) characterized by the high prevalence of germline mutations, including those affecting succinate dehydrogenase (SDH) subunits genes (A, B, C and D). SDHB mutations are associated with a poor prognosis in PPGL patients, whose treatments are limited. SDH is a TCA enzyme, which converts succinate into fumarate. SDH mutations lead to a loss of function of the enzyme, and thus an accumulation of succinate. Succinate is an oncometabolite inhibiting α-ketoglutarate-dependent dioxygenases. Alterations in several signaling pathways, induced by succinate accumulation, have allowed identification of potential new therapeutic targets. Since PPGL are very rare cancers, set up of clinical trials is complex and the development of preclinical/translational studies is crucial. In this context, my work aimed to: 1- establish and characterize new cellular models of stably invalidated SDHB PPGL (CRISPR-Cas9) 2- evaluate new treatments (alone/combined) 3- study serum succinate levels as an oncobiomarker of PPGL (diagnosis of SDH mutations, disease monitoring, treatment response) 4- identify new therapeutic targets by a metabolomic approach. Finally, the results obtained in this thesis work should allow to improve the knowledge of SDH mutated cancers, to propose new promising treatments and to propose new biomarkers to improve the management of patients.
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Submitted on : Wednesday, November 17, 2021 - 12:51:13 PM
Last modification on : Monday, December 13, 2021 - 9:17:26 AM


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  • HAL Id : tel-03419851, version 2


Constance Lamy. Impact des mutations SDH sur la réponse antitumorale et identification de nouveaux biomarqueurs. Pharmacologie. Université Paris-Saclay, 2021. Français. ⟨NNT : 2021UPASQ023⟩. ⟨tel-03419851v2⟩



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