AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer

Abstract

Ovarian carcinoma is the most deadly gynecological malignancy. Current chemotherapeutic drugs are only transiently effective and patients with advance disease often develop resistance despite significant initial responses. Mounting evidence suggests that anti-apoptotic proteins, including those of the inhibitor of apoptosis protein (IAP) family, play important roles in the chemoresistance. There has been a recent emergence of compounds that block the IAP functions. Here, we evaluated AT-406, a novel and orally active antagonist of multiple IAP proteins, in ovarian cancer cells as a single agent and in the combination with carboplatin for therapeutic efficacy and mechanism of action. We demonstrate that AT-406 has significant single agent activity in 60% of human ovarian cancer cell lines examined in vitro and inhibits ovarian cancer progression in vivo and that 3 out of 5 carboplatin-resistant cell lines are sensitive to AT-406, highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum resistance. Additionally, our in vivo studies show that AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice, suggesting that AT-406 sensitizes the response of these cells to carboplatin. Mechanistically, we demonstrate that AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin, suggesting that AT-406 has potential as a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.

Keywords: :

• Smac mimetic
• carboplatin
• chemosensitization
• ovarian cancer
• therapeutic agent

Disclosure of Potential Conflicts of Interest

Dr Shaomeng Wang owns stocks and stock options in Ascenta Therapeutics and serves as a consultant for Ascenta, which has licensed AT-406 from the University of Michigan for development. Dr Wang is an inventor on AT-406 and receives royalties from the University of Michigan. Other authors have no conflicts of financial interest to declare.

Acknowledgments

We thank excellent technical support of Ms. Rong Lu and Mr. Yin Xu at Mount Sinai School of Medicine, the Cooperative Human Tissue Network (CHTN) for providing human ovarian tissues. This work is supported by the funds from NIH-NCI (R01CA135158 to Q.Y.). Melissa Brunckhorst was supported by an institutional training grant (5T32CA078207–12). Dimitry Lerner is a fellow at the Gynecologic Oncology Program at Mount Sinai School of Medicine.