Current medical treatment options in dogs with cortisol-secreting adrenocortical tumors (ATs) are trilostane or mitotane. However, trilostane is a palliative treatment and has no effect on the tumor itself, while mitotane does have adrenocorticolytic activity, but can cause serious adverse effects. ATR-101, a new orally available drug, is known to have selective adrenocorticolytic activity in guinea pigs, dogs, monkeys, and humans, and is currently being tested in a phase II clinical trial for ATs in humans. ATR-101 is a selective and potent sterol-O-acyltransferase 1 (SOAT1) inhibitor, which leads to the accumulation of free cholesterol in adrenocortical cells, resulting in endoplasmic reticulum stress and ultimately leading to apoptosis. Inhibition of SOAT1 could be an interesting therapy option in dogs with ATs, but can only be useful if canine ATs express SOAT1.

The aim of this study was to determine whether the use of a selective SOAT1 inhibitor such as ATR-101 could have potential in the treatment of canine ATs. To this end, we evaluated the SOAT1 mRNA expression with RT-qPCR in 59 ATs (44 carcinomas and 15 adenomas) and 12 normal adrenals (NAs), and protein expression with immunohistochemistry (IHC) in 47 ATs (36 carcinomas and 11 adenomas) and 4 NAs. Slides were stained with polyclonal rabbit-anti-human antibody and antibody specificity was confirmed with western blot. A semiquantitative H-score for SOAT1 protein expression was calculated by multiplying the area of positive staining with the staining intensity grading score.

SOAT1 mRNA was detectable with RT-qPCR in all samples tested. No significant differences were found between NAs (mean fold change 1.05±0.31), adenomas (1.17±0.60) and carcinomas (1.76±1.39), but expression was more variable in ATs and in particular in carcinomas. No significant differences were found in protein expression between NAs (H-score 5.97±1.82), adenomas (5.41±2.03) and carcinomas (5.54±3.26), but carcinomas again showed more variable expression and three carcinomas had low to absent SOAT1 protein expression (H-score lower than one).

In conclusion, SOAT1 mRNA was present in all and SOAT1 protein in 94% of our samples, providing a solid base that a selective SOAT1 inhibitor could have great potential as a future treatment in canine ATs. To determine the effect of ATR-101 in canine ATs, further studies are warranted.

Disclosures

No disclosures to report.