CushiONS - Cushing’s syndrome: Optimizing Novel treatment Strategies

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Cushing’s syndrome (CS) is a serious endocrine disease in both humans and dogs that is associated with high morbidity and mortality rates. The most effective medical treatment so far is mitotane, however, mitotane’s toxic off-target effects limit its use. To improve its efficacy while reducing the side effects, drugs that work synergistically with mitotane, and therefore potentiate its effect at a low dosage, would be useful. In this study, we want to investigate how three potentially synergistic drugs combined with mitotane or with drugs with a similar mechanism of action as mitotane, affect canine adrenocortical cells.

Seeing that the canine adrenal gland has the same anatomy and biology as the adrenal gland in humans, and the incidence of CS in dogs is ~1000 times higher than in humans, the dog is an excellent model for further research on mitotane in CS.

We expect that the information gained by our proposed research will ultimately improve the medical treatment of CS in both humans and dogs and prolong their survival times.

Hypercortisolism, often referred to as Cushing’s syndrome (CS), is a serious endocrine disorderthat results from chronic exposure to excessive glucocorticoids. Naturally occurring CS is one of the most common endocrine disorders in dogs, with an incidence of 1 to 2 per 1000 dogs per year. In contrast, in humans the incidence of naturally occurring CS is 1 to 5 per million people per year. The relatively low incidence of human CS hinders research on new treatment options. In both humans and dogs, naturally occurring CS is in about 70-85% of cases caused by an ACTH-producing pituitary adenoma (pituitary-dependent hypercortisolism; PDH). In the remaining 15-20%, there is a functional adrenocortical tumor (ACT), which can be either an adrenocortical adenoma (ACA) or, more commonly, an adrenocortical carcinoma (ACC). If not properly treated, both forms of CS are associated with high morbidity and mortality rates, both in humans and in dogs.

Surgical removal of either the pituitary tumor or the ACT is a good treatment option, since this aims for definite cure. However, this is not without risks, not generally available (especially in veterinary clinics), and not suitable for every patient. Moreover, surgical failure can occur, or metastases can be present in cases with an ACC. Medical treatment therefore plays an important role, either as primary or adjuvant treatment post-surgery. Even with adjuvant treatment, humans with metastatic ACC have a 5-year survival rate of less than 15%.

The only medical treatment that is currently approved for metastatic ACC in humans is the adrenocorticolytic and steroidogenesis inhibiting drug mitotane (o,p’-DDD),which can also be used for ACTs in dogs. Mitotane has also been used effectively to reduce cortisol production in PDH in both humans and dogs, but because it can induce serious side-effects and requires diligent monitoring, other (safer) steroidogenesis-inhibiting drugs are preferred over mitotane in PDH. For ACTs, the added advantage of mitotane is that it can destroy adrenocortical cells, but it is effective in only a third of treated humans with ACCs. Most people whose ACC doesn’t respond have too low plasma mitotane levels, but mitotane’s toxic off-target effects limit dosage increases.

However, mitotane’s exact mechanism of action remains unclear.

What we aim to do

In order to improve mitotane’s efficacy while also reducing side-effects, drugs that work synergistically with mitotane and therefore strengthen its effect at low dosages, might prove useful for both PDH and ACTs. Alternatively, other drugs with similar mechanisms but fewer off-target effects could improve drug response.

The ultimate aim of this research is to improve the medical treatment of CS for both humans and dogs, and in particular to prolong survival in case of ACC.