The recent identification of genetic mutations linked to Cushing disease (CD) and its unbalanced molecular mechanisms has opened new potential therapeutic avenues for an illness with a large unmet medical need.
In the study, “Recent advances in understanding Cushing disease: resistance to glucocorticoid negative feedback and somatic USP8 mutations,” that appeared in F1000Research, researchers from England’s University of Sheffield Medical School reviewed the molecular mechanisms involved in CD.
The disease is caused by a pituitary gland tumor, called corticotroph adenomas, that secretes high levels of the ACTH hormone, which raises cortisol levels in blood and urine. Most clinical features of CD, including diabetes, osteoporosis, life-threatening infections and psychiatric and cognitive changes, are recognized as adverse effects of high cortisol levels, or hypercortisolism.
Preclinical studies have shown that these tumors often express high levels of testicular orphan nuclear receptor 4 (TR4) and heat shock protein 90 (HSP90). Studies show that both help regulate ACTH production in corticotroph adenomas. Preclinical studies using CD mouse models have already demonstrated the therapeutic potential or TR4 and HSP90 inhibitors, which reduce ACTH levels.
A more recent study showed that 35 to 62 percent of sporadic cases of corticotroph adenomas carried genetic variants of the USP8 gene, which was found to increase expression of epidermal growth factor receptor (EGFR). This protein is highly expressed in up to 75 percent of corticotroph tumors, and is linked to cell proliferation, ACHT production and increased tumor aggressiveness.
In vitro studies in which researchers genetically modified USP8-mutated corticotroph tumor cells to halt the expression of the mutant USP8 showed a marked decrease in both EGFR and ACTH levels.
“Molecules involved in USP8/EGFR and TR4 signaling pathways as well as selective inhibitors of HSP90 are emerging as attractive therapeutic targets, especially as no ideal treatment exists for treating corticotroph adenomas not cured by surgery, possibly paving the way for personalized medicine in the future,” researchers wrote. “The outcomes of clinical trials using compounds that target these pathways are keenly awaited.”
More studies and clinical trials are still required to further assess the efficacy and tolerability of such therapeutic strategies for CD.