Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis

Lussey-Lepoutre, Charlotte; Buffet, Alexandre; Morin, Aurélie; Goncalves, Judith; Favier, Judith

doi:10.1007/s00441-018-2797-y

Cited by 17 publications

(14 citation statements)

References 99 publications

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“…Given the rarity of MPPG (estimated incidence is less than one per million people per year), it is almost impossible to have multiple clinical trials testing a variety of drugs or drug combinations concomitantly. Several knockout mouse models for SDHB and other pheochromocytoma- and paraganglioma-related genes leading to activation of HIF2α (that is, von Hippel-Lindau and the mitochondrial enzymatic complex II subunit D genes) have not been demonstrated to mimic the human phenotype 21 , 22 . The lack of a reliable preclinical animal model is a major drawback that has impaired the screening of available drugs and drug combinations.…”

Section: Challenges In the Discovery Of New Medications To Treat Mppgmentioning

confidence: 99%

Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors

Toledo¹,

Jiménez

2018

F1000Res

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Inactivating mutations of the succinate dehydrogenase subunit B ( SDHB) gene and the subsequent stabilization and activation of the hypoxia-inducible factor 2-alpha (HIF2α) unit are recognized hallmarks associated with the development of metastatic pheochromocytomas and paragangliomas (MPPG). Despite this discovery, the development of systemic therapies for patients with MPPG has been very slow. The rarity of the disease, the lack of preclinical animal models, and the impracticable development of large clinical trials has hindered the therapeutic progress for MPPG. Chemotherapy and low-specific activity 131meta-iodo-benzyl-guanidine (MIBG) (manufactured by simple isotope exchange methodology) led to positive clinical responses in about a third of patients. Molecular targeted therapies were introduced into oncological clinical practice at the beginning of the 21st century. These therapies have been demonstrated to be effective for patients with cancers that previously exhibited limited responses to systemic chemotherapy, such as kidney and thyroid carcinomas and pancreatic neuroendocrine tumors. The pathogenesis of MPPG overlaps in some way with the pathogenesis of kidney, medullary thyroid, and pancreatic neuroendocrine carcinomas, providing scientific support to explore molecular targeted therapies such as tyrosine kinase and HIF inhibitors.

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Section: Challenges In the Discovery Of New Medications To Treat Mppgmentioning

confidence: 99%

Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors

Toledo¹,

Jiménez

2018

F1000Res

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“…14 Though there have been multiple attempts to develop mouse models that mimic SDH-related hereditary PPGL, no successes have been reported. 3,[15][16][17][18] As in humans, homozygous SDH-loss in mice is an embryonic lethal condition. Unlike humans, heterozygosity for SDHx mutations does not predispose mice to PPGL.…”

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confidence: 99%

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

et al. 2020

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Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH + glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH + cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.

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“…Interestingly, Bausch et al also observed other additional malignant neoplasms in 25% of patients with TMEM127 disease (colon cancer, acute myeloid leukemia, pancreatic adenocarcinoma, malignant melanoma and parathyroid adenoma, but no breast cancer). Against this background, we believe it is key to consider the possibility of hereditary disease when an endocrinologist is confronted with coexisting PCC/PGL and pituitary adenoma (’3PAs’) and genetic workup is recommended regarding the available PCC/PGL-related gene panel ( 3 , 5 , 22 , 23 ). In our patient the clinical consequence of the described TMEM127 mutation is unknown.…”

Section: Discussionmentioning

confidence: 99%

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

Stütz

Korbonits

Kothbauer

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary The coincidence of a pheochromocytoma or paraganglioma and a pituitary adenoma in the same patient is a rare condition. In the last few years SDHx and MAX mutations have been identified and discussed as a potential causal connection in cases of coincidence. We describe a case of a middle-aged female patient which presented with acromegaly, a growth hormone-secreting pituitary adenoma and a symptomatic neck paraganglioma. The patient was cured by surgery from both the pituitary tumour and the paraganglioma and is well after ten years follow-up. Due to the unusual coexistence of two neuroendocrine tumours, further molecular genetic testing was performed which revealed a variant in the TMEM127 gene (c245-10C>G). Learning points: Pheochromocytoma/paraganglioma and coexisting functioning pituitary adenoma are a very rare condition. An appropriate treatment of each tumour entity with a multi-disciplinary approach and regular follow-up is needed. The possibility of a hereditary disease should be considered and genetic workup is recommended. Genetic testing should focus primarily on the genes with mutations related to pheochromocytomas and paragangliomas. Next-generation sequencing with multi-gene panel testing is the currently suggested strategy. Genes associated with paragangliomas and pituitary adenomas are SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and MEN1, while case reports with VHL, RET and NF1 may represent coincidences. Variants of uncertain significance may need ongoing vigilance, in case novel data become available of these variants.

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Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis

Cited by 17 publications

References 99 publications

Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors

Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

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