Abstract
Abstract High-grade serous ovarian cancers (HGSOC) are deadly gynecologic malignancies that are often metastatic at presentation with a 5 year survival rate of 30-40%. While first-line treatment with carboplatin is often efficacious, disease usually recurs within 6-16 months. With successive rounds of chemotherapy a carboplatin resistant phenotype dominates. Emergence of carboplatin resistance is often thought to be an acquired property of HGSOC but we have recently demonstrated that carboplatin resistance is an innate property of all HGSOCs and inherent to a population of CA125 negative tumor cells with stem properties. The CA125 negative tumor cells comprise a minor population of HGSOCs but evade carboplatin therapy based on in vitro and in vivo drug assays and analysis of primary patient specimens obtained pre and post chemotherapy. We think that targeting the CA125 negative carboplatin resistant serous cancer stem cells (SCSC) will be essential for achieving long-term remissions in this disease. To explore mechanisms of therapy resistance in these cells, the transcriptome of SCSC isolated from 10 primary chemo-naïve HGSOCs was analyzed. An increase in the message levels of inhibitor of apoptosis proteins cIAP1 and cIAP2 was detected in the SCSC. Here we examine the efficacy of the drug Birinapant, a SMAC mimetic that targets cIAPs, in sensitizing human HGSOC to carboplatin therapy. In vitro analysis of 9 primary chemo-naive human HGSOC specimens demonstrated that combined therapy with Birinapant and carboplatin eliminated the chemo-resistant SCSC in 6 specimens, all of which had high levels of cIAP in their SCSC. Next, subcutaneous xenografts were established from 3 independent low-passaged cell lines derived from primary chemo-naive human HGSOCs. In vivo co-treatment of these tumors with Birinapant and carboplatin resulted in significantly diminished tumor burden and a durable response to treatment compared to either therapy alone. These results were further confirmed in a more physiologic intra-peritoneal tumor model. The combination of Birinapant and carboplatin was then tested in targeting in vivo xenografts derived directly from two chemo-resistant human HGSOCs. This co-therapy was efficacious in significantly decreasing tumor burden in the chemo-resistant HGSOC with high cIAP in its SCSC but ineffective in eliminating the tumor where a lower level of cIAP (the Birinapant target) was found in its cancer stem population. Collectively, these results provide proof-of-principle that pharmacologic targeting of the SCSC can be an effective strategy for sensitizing them to carboplatin resulting in a potentially durable therapeutic response in primary and recurrent HGSOC. We think these pre-clinical findings merit testing the efficacy of this combination therapy in clinical trials treating patients with HGSOC with high levels of cIAP in their tumor stem cells. Note: This abstract was not presented at the meeting. Citation Format: Deanna Janzen, Ekaterian Tiourin, Justin Salehi, Jing Lu, Matteo Pellegrini, Sanaz Memarzadeh. Targeting CA125 negative high grade serous ovarian cancer stem cells can result in a dramatic reduction in tumor burden. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5331. doi:10.1158/1538-7445.AM2015-5331
Published Version
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