Efficacy of birinapant in combination with carboplatin in targeting platinum‑resistant epithelial ovarian cancers

Singh,Tanya; Neal,Adam; Dibernardo,Gabriella; Raheseparian,Neela; Moatamed,Neda A.; Memarzadeh,Sanaz

doi:10.3892/ijo.2022.5325

Efficacy of birinapant in combination with carboplatin in targeting platinum‑resistant epithelial ovarian cancers

Authors:
- Tanya Singh
- Adam Neal
- Gabriella Dibernardo
- Neela Raheseparian
- Neda A. Moatamed
- Sanaz Memarzadeh
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Affiliations: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Published online on: February 21, 2022 https://doi.org/10.3892/ijo.2022.5325
Article Number: 35
Copyright: © Singh et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Patients diagnosed with epithelial ovarian cancers (EOCs) often suffer from disease relapse associated with the emergence of resistance to standard platinum‑based chemotherapy. Treatment of patients with chemo‑resistant disease remains a clinical challenge. One mechanism of chemoresistance includes overexpression of pro‑survival proteins called inhibitors of apoptosis (IAP) which enable cancer cells to evade apoptosis. Due to their anti‑apoptotic activity, association with poor prognosis, and correlation with therapy resistance in multiple malignancies, IAP proteins have become an attractive target for development of anticancer therapeutics. Second mitochondrial activator of caspase (SMAC) mimetics are the most widely used IAP antagonists currently being tested in clinical trials as a monotherapy and in combination with different chemotherapeutic drugs to target different types of cancer. In the present study, the antitumor efficacy of combination therapy with birinapant, a bivalent SMAC mimetic compound, and carboplatin to target platinum‑resistant EOC cells was investigated. A 3D organoid bioassay was utilized to test the efficacy of the combination therapy in a panel of 7 EOC cell lines and 10 platinum‑resistant primary patient tumor samples. Findings from the in vitro studies demonstrated that the birinapant and carboplatin combination was effective in targeting a subset of ovarian cancer cell lines and platinum‑resistant primary patient tumor samples. This combination therapy was also effective in vitro and in vivo in targeting a platinum‑resistant patient‑derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum‑resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.

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