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

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.

SLC11A1 as a stratification indicator for immunotherapy or chemotherapy in patients with glioma

“…Birinapant has extensive IAP antagonistic effects. Birinapant can cause rapid degradation of cIAP1, cleavage of PARP, activation of caspase, and inhibition of activation of NF-κB ( 45 ). The use of clofarabine and birinapant in gliomas has not been reported.…”

Profiling ovarian cancer tumor and microenvironment during disease progression for cell-based immunotherapy design

“… 1 , 4 , 5 Confounding this is the fact that many OC cases will become platinum resistant and no longer respond to traditional therapies. 7 , 13 , 88 In this case, alternative approaches that are effective in treating OC patients is an unmet clinical need. 1 , 4 , 5 , 6 , 7 , 12 , 13 Here we have profiled a series of primary OC patient samples in the hopes to better understand the antigenic and environmental factors that distinguish chemonaive from recurrent, platinum-sensitive from platinum-resistant states, and how to more effectively target OC.…”

Overview of the progress and prospects of SMAC mimetics in cancers: Is it a silver bullet?

“…The combined treatment with birinapant (a SMAC mimetic compound) and carboplatin was found to be effective in various platinum-resistant EOC cell lines, in tumor samples and in PDX models. To simulate in-vivo responses, 3D organoid bioassay was successfully employed to study the combined effect of birinapant and carboplatin, which demonstrated improved anticancer efficacy that suggests the applicability of this model in pre-clinical studies (18).…”