OR14-5 ATR-101, a Selective ACAT1 Inhibitor in Development for Adrenocortical Carcinoma, Disrupts Steroidogenesis and Causes Apoptosis in Normal Canine Adrenals

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR14-Adrenal Tumors: Novel Causes and Mechanisms
Translational
Sunday, June 22, 2014: 11:30 AM-1:00 PM
Presentation Start Time: 12:30 PM
W196 (McCormick Place West Building)
Marc B Bailie, D.V.M., Ph.D.1, Martin D Phillips, MD2, Raili Kerppola, PhD2, James R Herman, PhD1, Paul G Pearson, PhD3, Gary D Hammer, MD, PhD4, Randall W Whitcomb, MD2, Julia Owens, PHD2 and Stephen W Hunt III, PhD2
1INDS, Ann Arbor, MI, 2Atterocor, Inc., Ann Arbor, MI, 3Pearson Pharma Partners, Westlake Village, CA, 4University of Michigan, Ann Arbor, MI
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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