ATR-101 and ER Stress-Inducing Chemotherapeutic Agents Synergize to Induce Cytoxicity in Adrenocortical Cancer Cells

Presentation Number: MON 396
Date of Presentation: April 3rd, 2017

Christopher Ryan LaPensee*1, Stephen W Hunt III2 and Gary D Hammer1
1University of Michigan, Ann Arbor, MI, 2Atterocor, Inc., Ann Arbor, MI

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex, with an estimated worldwide annual prevalence of 1 to 2 cases per million, accounting for 0.2% of cancer deaths annually. ACCs are highly aggressive with many patients presenting with metastases upon diagnosis due to difficulty of detection. Therapeutic options for the treatment of ACC are limited. While mitotane and cytotoxic chemotherapy are often used to treat metastatic ACC, the efficacy of most regimens is extremely toxic and poorly tolerated, leaving an unmet medical need for new treatments for ACC. ATR-101 is a novel, oral drug candidate currently in development for the treatment of Adrenocortical Cancer (ACC). ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol. Our previous studies determined that inhibition of ACAT1 by ATR-101 in the H295R human ACC cell line increases free cholesterol, which causes dysregulation of ER calcium, activation of ER stress and the Unfolded Protein Response (UPR), ultimately leading to apoptosis. Chemotherapeutic agents directed at an individual target frequently can show limited efficacies and poor safety and resistance profiles. Thus, drug combinations are widely used in treating complex diseases such as cancer, HIV and cardiovascular diseases. The most prominent benefit of a drug combination is the synergy effect among different drugs, where the overall therapeutic effect of the combination is greater than the sum of effects caused by individual components. In cancer therapy, an effective drug combination may target pathways that are sensitive inhibition or activation in disease. Here, we examined the synergy between ATR-101 and bortezimib, a therapeutic inhibitor of the 26S proteasome and activator of the UPR, as well as thapsigargin, an inhibitor of the calcium pump SERCA2B that leads to ER stress, to induce ACC cell death. Treatment of H295R cells with increasing amounts of ATR-101, bortezimib, or thapsigargin alone defined sub-toxic and toxic concentrations. Co-incubation of H295R cells with sub-toxic concentrations of ATR-101 and either bortezimib or thapsigargin, induced a significant increase in ACC cell death. These studies suggest that ATR-101 may synergize with other inducers of ER stress and the UPR to improve patient outcome in ACC.

 

Disclosure: SWH III: , Atterocor Inc. GDH: Founder, Atterocor Inc. Nothing to Disclose: CRL