According to a publication from Healio, recent breakthroughs in medical science have renewed hopes of finding a cure for the rare Cushing disease. Dr. Shlomo Melmed, dean and executive Vice President of the famous Los Angeles Cedars-Sinai Medical Center, spoke of past difficulties with the diagnosis and treatment of Cushing disease at a conference keynote in Los Angeles.

About Cushing Disease

Cushing disease, or Cushing syndrome, is caused by an overabundance of the stress hormone cortisol. That’s not to say that a scary movie is enough to give you Cushing disease – rather, the symptoms of Cushing disease develop over time after prolonged exposure to elevated cortisol levels.

These elevated cortisol levels are usually caused by the presence of a benign tumor on the pituitary gland called pituitary adenoma. The pituitary gland is a vitally important endocrine gland, and is responsible for controlling the release of many of the body’s most important hormones. When an adenoma forms on the gland, it can erroneously stimulate the uncontrolled release of ACTH – a hormone that triggers the production of cortisol in the adrenal glands.

Over time, exposure to unchecked cortisol levels can lead to changes in physical and mental state. People developing Cushing disease may develop weight gain, thin skin, or a “buffalo hump” of fat deposits that settle between the shoulders.

Perhaps more debilitating, though, are the psychological aspects of the condition. Individuals with Cushing’s disease frequently develop depression, anxiety, and mood swings. If unmanaged, Cushing disease can even be fatal.

Hope for a Cure

Difficulties treating Cushing disease begin right at diagnosis. Many of the hallmark physical symptoms of the disease, such as weight gain, overlap with other common conditions like obesity, hypertension, or diabetes. “There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said during his presentation. That means most doctors probably aren’t expecting to see many cases of Cushing’s disease, and may even fail to identify a given case until it’s too late to effectively treat.

Additionally, Dr. Melmed notes that about 10% of the population has a pituitary adenoma, though most are quite small and nearly half aren’t even visible. Popular existing methods for removing pituitary adenoma include surgery and radiation, which can have serious side effects and often fail to achieve lasting remission. How, then, can we still hope to treat Cushing’s patients?

A 2011 study of fish provided an unlikely but potential answer. Zebrafish, when injected with a gene to generate pituitary adenoma, displayed symptoms remarkably similar to those of Cushing patients – elevated cortisol levels, diabetes, and cardiovascular disease. While searching for a way to “shut off” the overactive ACTH, Melmed and his team discovered that cyclin E inhibitor R-roscovitine repressed the expression of POMC, the pituitary chemical precursor to ACTH, in zebrafish.

In fish, mouse, and in-vitro human cell tests, R-roscovitine was associated with blocked ACTH production. A limited open study found that some Cushing’s patients administered R-roscovitine over a period of four weeks experienced a normalization of cortisol levels.

A phase 2 arm of the study, funded by FDA Office of Orphan Products Development, is in development and may occur some time in the next few years. Because of the rarity of Cushing’s, finding a statistically-meaningful pool of participants is a challenge in and of itself. “[The] zebrafish model was published in 2011, and we are now in 2019,” Melmed said of his research. Eight years is a long time to prepare an animal study – a prescient reminder that human research is a different animal entirely (no pun intended).

Though R-roscovitine seems potentially promising, updates could be years away.

Melmed estimates that as much as 10% of the population has a type of benign tumor that can sometimes lead to Cushing syndrome. Why do you think this research is so critical? Do you think it’s worth waiting 8 years to take an animal study to phase 2 trial? Patient Worthy wants to hear from you!