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OR14-Adrenal Tumors: Novel Causes and Mechanisms
Presentation Start Time: 12:30 PM
W196 (McCormick Place West Building)
ATR-101 is a novel small molecule therapeutic in clinical development for the treatment of adrenocortical carcinoma (ACC). ACC is a rare and highly aggressive endocrine cancer of the adrenal cortex with an incidence of about 2 per million population. ACC is usually diagnosed at a late stage resulting in very poor patient prognosis. Many patients with ACC have treatment-resistant Cushing’s syndrome. The only approved therapy for ACC, mitotane, has limited effectiveness and is poorly tolerated. There is a significant need for new therapies to treat ACC. ATR-101 is a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase). ACAT1 catalyzes cholesterol ester formation from cholesterol and long-chain fatty acyl-CoA and, in the adrenal cortex, is particularly important in creating a reservoir of substrate for steroid biosynthesis. As ACCs derive from the adrenal cortex and often retain many tissue-specific characteristics, we studied the effects of ATR-101 in normal canine adrenals as a model to understand the molecular mechanism of the compound. Normal beagles were treated for either 7 or 14 days via once daily oral administration of ATR-101 and systemic and tissue-specific exposure, target tissue pharmacology, adrenal function, and histologic changes in the adrenals were evaluated. ATR-101 plasma exposure was dose related and ATR‑101 levels were highest in adrenals compared to other tissues. Cholesterol ester levels were decreased in the adrenals demonstrating that ATR-101 functions as an ACAT1 inhibitor in the target tissue. ATR-101 treatment led to rapid, dose-dependent decreases in ACTH-stimulated cortisol levels and all other steroids and steroid intermediates assessed, consistent with ATR-101-mediated inhibition of ACAT1 and disruption of substrate availability for steroid biosynthesis. At the termination of the treatment period, ATR-101 induced histological changes in the adrenals including significant apoptosis in the zona reticularis and zona fasciculata. The results of this study provide insight into unique attributes of ATR-101 and support its development as a novel therapeutic for the treatment of ACC. ATR-101 is in a human phase 1 clinical trial for ACC (ClinicalTrials.gov Identifier: NCT01898715.)
Disclosure: MBB: Consultant, Atterocor, Inc.. MDP: Employee, Atterocor, Inc, Employee, Atterocor, Inc. RK: Founder, Atterocor, Inc.. JRH: Consultant, Atterocor, Inc.. PGP: Consultant, Atterocor, Inc.. GDH: Founder, Atterocor, Inc.. RWW: Consultant, Atterocor, Inc.. JO: Founder, Atterocor, Inc., Founder, Atterocor. SWH III: Chief Scientific Officer, Atterocor, Inc., Chief Scientific Officer, Atterocor.
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