It is truly an exciting time to be involved in the study of the molecular mechanisms of Cushing’s! From a patient’s perspective, useful treatments for Cushing’s based on new findings will be a long time in coming, however it is highly encouraging to know that many excellent researchers are involved in this research. The Spring, 2014 issue of this newsletter covered a number of developments in understanding the genetics of adrenal tumors, bilateral adrenal hyperplasia and pituitary tumors. Since that time, several additional studies have appeared in the literature regarding ACTH secreting pituitary tumors.
In early December, 2014, a study by Reinke, M. (1) and many others cooperating across international borders reported that 6 out of 17 (35%) ACTH secreting tumors studied showed somatic (not inheritable) mutations in the USP8 gene. These mutations were shown to increase the activity of a receptor* for an important growth factor called epidermal growth factor (EGF) which stimulates the secretion of ACTH by the tumors. In February, 2015 Ma, ZY (2) and others in China found similar mutations in the USP8 gene in 67 of 108 (62%) ACTH secreting pituitary tumors. The USP8 mutations were found mostly in smaller tumors compared to larger tumors. Other types of pituitary tumors were also studied and USP8 mutations were not found in 150 non-ACTH secreting pituitary tumors. Further work in cell culture with USP8 mutated cells showed increased levels of the EFG receptor and that a specific blocker of the EFG receptor called gefitinib could decrease ACTH secretion. The authors concluded, “Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing’s disease.” This finding opens the future possibility of new drug therapy targeting EGF receptor overfunction in these tumors.
In February, 2015 a research article by Riebold, M. (3) and others from Germany, reported on the potential for the active component of milk thistle, silibinin, to partially restore glucocorticoid feedback sensitivity to ACTH secreting pituitary tumor cells. This was done using cells in culture and a mouse model. While this is potentially an exciting development, detailed clinical studies need to be conducted before this work finds clinical applications in humans. Dr. Stratakis from NIH states “Human studies need to be done with a range of doses of the active component of milk thistle, silibinin, to see if there would be an effect on cortisol secretion. It is not unusual for compounds that appear safe in the short term to have high toxicity in chronic administration even in lower concentrations”. Cushing’s is a serious medical disorder that should be treated promptly. At the present time, there is no “natural” cure for Cushing’s.
In addition, an entire recent issue of the journal Pituitary, published by the Pituitary Society was dedicated to Cushing’s. Likewise, the February, 2015 issue of the Journal of Neurosurgery – Neurosurgical Focus, was dedicated to Cushing’s.
* Receptors are proteins through which growth factors and hormones exert their effects on cells.
Authors: Karen Campbell and Dr. André Lacroix, Spring, 2015
Editor’s Note: Dr. André Lacroix is Professor of Medicine in Endocrinology and Metabolism at the University of Montreal Teaching Hospital (CHUM), Montreal, Canada. Karen Campbell is a Director of the CSRF.
- Reincke, M. et al, Nat Genet. 2015 Jan;47(1):31-8. doi: 10.1038/ng.3166. Epub 2014 Dec 8.
- Ma, ZY. Et al, Cell Res. 2015 Mar;25(3):306-17. doi: 10.1038/cr.2015.20. Epub 2015 Feb 13.
- Riebold, M., et al, Nat Med. 2015 Mar;21(3):276-80. doi: 10.1038/nm.3776. Epub 2015 Feb 9.