Abstract LB-131: Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells

Abstract

Abstract High-grade serous ovarian cancers (HGSOCs) contain CA125-negative cancer-initiating cells resistant to standard platinum therapy. High expression of cellular inhibitors of apoptosis proteins (cIAPs) in these platinum resistant HGSOC initiating cells causes resistance to apoptosis despite platinum-induced DNA damage. cIAPs can be degraded with the addition of birinapant, a SMAC-mimetic, sensitizing cancer initiating cells to carboplatin and resulting in their elimination. Using in vitro drug assays, we demonstrate that more than half of human HGSOCs (13/23 independent samples) can be targeted with birinapant and carboplatin co-therapy. Importantly, treatment with this co-therapy eliminated tumor cells irrespective of their clinically-defined platinum sensitivity suggesting that this therapeutic approach could be efficacious with patient who have platinum sensitive and/or resistant disease. Pre-clinical trials in mice bearing intra-peritoneal low-passage human-derived HGSOC cell lines demonstrate that birinapant and carboplatin co-therapy significantly improves overall survival. A vast majority of co-therapy treated mice are still alive, 5 months after all animals treated with vehicle or carboplatin monotherapy have succumbed to tumor. Given that co-therapy was efficacious in approximately 50% of HGOSCs, evaluation of biomarkers that can predict this response are clinically relevant. The expression of cIAP levels were quantified using western blot and then immunohistochemistry in the CA125 negative fraction of our 23 clinical samples. We found that expression of ≥24ng of cIAP in the CA125-negative HGSOC cell lysate could accurately predict response to co-therapy with 100 percent accuracy. Detection and quantification of cIAP in CA125 negative cells by immunohistochemistry (IHC) could also predict a response to co-therapy with 95 percent accuracy. We report on careful analysis of two sets of biomarkers specifically measuring druggable targets in ovarian cancer initiating cells that could predict a response to co-therapy with birinapant and carboplatin. This therapeutic approach, that can overcome platinum resistance in ovarian cancer initiating stem cells, will be tested in an upcoming clinical trial alongside our proposed companion diagnostic biomarkers of response. Citation Format: Vincent La, Rachel Fujikawa, Deanna Janzen, Liat Bainvoll, Sanaz Memarzadeh. Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-131.