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Current Clinical and Pre-Clinical Progress in Cushing's Disease

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Cushing’s disease, the most frequent form of hypercortisolism, is caused by corticotroph pituitary adenomas secreting excessive amounts of adrenocorticotropic hormone. Only a small number of corticotropinomas have a hereditary background whereas the vast majority of tumors develop sporadically. Moreover, in ...

Cushing’s disease, the most frequent form of hypercortisolism, is caused by corticotroph pituitary adenomas secreting excessive amounts of adrenocorticotropic hormone. Only a small number of corticotropinomas have a hereditary background whereas the vast majority of tumors develop sporadically. Moreover, in corticotroph adenomas, an emerging number of epigenetic changes have been detected which are thought to play an important role in corticotropinoma pathogenesis. Epigenetic modifications include multiple aberrant methylation/ demethylation patterns of different genes and altered acetylation/ deacetylation of DNA histones.

Corticotroph tumors arise initially as benign microadenomas and can then transform in rare cases to a growth arrested senescent tumor, but mostly progress slowly to an increasingly aggressive tumor phenotype and finally form a metastasizing corticotroph carcinoma. Multivariate analyses between the different stages of corticotropinoma progression have identified a considerable number of differential expressed factors whose role and mechanisms in corticotropinoma development still have to be investigated.

The diagnosis of Cushing’s disease still occurs very late as it is based on the initially unspecific clinical signs of hypercortisolism. Regarding the therapy of Cushing’s disease, surgical resection is still the first line treatment of corticotropinomas. Meanwhile, a number of alternate and supplementary therapeutic options have been established and few more treatment concepts are currently approved in running clinical trials. At the same time, new drug targets involved in glucocorticoid resistance of corticotropinomas have recently been identified.

Cushing’s disease is associated with multiple hypercortisolism related-comorbidities such as metabolic and neuropsychiatric disorders strongly impairing the patients’ quality of life (QoL) which, often does not normalize even after successful therapy.

Within this Research Topic on the “Current Clinical and Pre-clinical Progress in Cushing’s Disease” hosted by the Pituitary Endocrinology Section of Frontiers in Endocrinology, an overview about recent advances in understanding the pathogenesis of corticotropinomas and the translation of these findings into clinical practice will be presented. To this end, experts of different areas of pre-clinical and clinical research on Cushing’s disease are welcomed to submit review articles summarizing current developments.

Those developments include, but are not limited to:

_ The new WHO-classification of pituitary adenomas distinguishing pituitary tumors through their key transcription factors (i.e., this has led to (1) changes in corticotropinoma subtype classification and (2) has identified specific corticotroph tumor entities with high risk of developing an aggressive tumor phenotype);

_ Novel insights into the genetics of hereditary corticotropinomas and, in particular, about the recently detected recurrent genetic abnormalities in sporadic corticotroph tumors such as USP8, USP48 and BRAF mutations;

_ The putative mechanisms of action following the genetic alterations and their contribution in corticotropinoma initiation and progression;

_ Recently described changes of methylation/ acetylation in corticotropinomas and their effect in corticotroph tumor genesis and progression;

_ Currently detected aberrant expression of non-coding RNAs (miRNA, lncRNA, circular RNA) and their role in corticotropinoma initiation and development;

_ Multivariant analyses between the different stages of corticotropinoma progression and the related differentially expressed factors whose play a role in corticotropinoma development;

_ The role of several factors identified as putative prognostic markers in particular for predicting post-operative corticotropinoma recurrence;

_ Actual treatment regimens of Cushing’s disease and future therapeutic options (i.e., these latter also include new concepts in restoring the disturbed glucocorticoid negative feedback in corticotropinomas); and

_ Underlying mechanisms of Cushing’s disease related comorbidities and how related treatment should further improve.


Keywords: Cushing's disease, Pathogenesis, Genetic/Epigenetic Alterations, Corticotrpinoma Progression, Novel Therapy


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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