Sanaz Memarzadeh, MD, PhD
Preclinical findings showed that the combination of the investigational agent birinapant and carboplatin could eliminate platinum-resistant, high-grade serous carcinoma (HGSC) ovarian tumor cells.
In results published in Precision Oncology
, Sanaz Memarzadeh, MD, PhD, director of the G.O. Discovery Lab and member of the UCLA Jonsson Comprehensive Cancer Center, found that combining birinapant and carboplatin could destroy HGSC cells with high cIAP levels in vivo and in animal models.
Median overall survival (OS) was twice as long for mice given the combination compared with monotherapy with carboplatin or birinapant (P
"I believe that our research potentially points to a new treatment option,” Memarzadeh said in a release. “In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”
Previous studies have shown that a synthetic SMAC mimetic and IAP antagonist could degrade platinum resistance in tumor cells with high levels of cellular inhibitor of apoptosis proteins (cIAP) 1 and 2. Memarzadeh et al determined that a threshold midpoint of 22.4 ng cIAP (threshold range, 19.1-25.8 ng cIAP) in 20 μg cell lysate identified which samples were combination-sensitive and which were resistant with 100% accuracy (P
To determine whether the combination could improve OS in physiologic models, researchers established 2 cell lines, S8-GODL and S9-GODL, from primary patient HGSCs. Memarzadeh et al noted that, in previous studies, a minor platinum-resistant population had been detected even in platinum-sensitive HGSCs, so they also analyzed the platinum-sensitive cell lines S1-GODL and Ovcar-3.
Researchers first examined response to the combination in all 4 cell lines with an in vitro organoid bioassay that used 2 independent tests: 1 an assessment of cell survival using flow cytometry, the other an organoid formation from cells surviving therapy. S9-GODL and S1-GODL cells were predicted to be sensitive to the combination while S8- GODL and Ovcar-3 cells were predicted to be resistant.
NSG female mice were injected with 2.5 × 105
HGSC cells and tumor-bearing mice were randomly assigned to 4 weeks of placebo, twice-weekly 30 mg/kg birinapant, once-weekly 50 mg/kg carboplatin or combination therapy with birinapant and carboplatin. Mice were observed until they reached NIH-defined end-point criteria.
OS for mice with platinum-resistant S9-GODL tumors was double that of mice in the combination arm compared with the other groups (P ≤.0002). Researchers did not observe a survival benefit for the combination in mice with S8-GODL tumors (P
≥.08). Monotherapy with birinapant or carboplatin did not increase OS of mice carrying either tumor cell line compared with placebo.
“Our results suggest that the treatment is applicable in some, but not all, tumors,” Rachel Fujikawa, a student in Memarzadeh's lab and a coauthor of the study, said in a statement.
The combination was associated with a doubling of median OS in mice with platinum-sensitive S1-GODL tumors compared with carboplatin (P
= .01). Similarly, S1-GODL tumor cells responded to the com sensitive. There was no treatment affect associated with the combination observed in mice with platinum-sensitive Ovcar-3 tumors (P
Carboplatin monotherapy improved OS compared with placebo in both the S1-GODL (P
= .0734) and Ovcar-3 (P
= .0068) groups. Birinapant monotherapy had no impact on OS in either group.
“Survival assays in mice bearing S9-GODL tumors derived from a platinum-resistant carcinoma demonstrate that platinum-resistant cancers can be effectively treated with carboplatin as long as a platinum-sensitizing agent tailored to the tumor is co-administered,” the researchers wrote. “Survival assays in mice bearing platinum-sensitive tumors provide further proof that eradication of even the minor population of platinum-resistant cells found in these carcinomas is required for achieving long-term remissions.”
Memarzadeh et al determined that birinapant overcomes platinum resistance in about 50% of tumor cells by testing a cohort of 23 primary patient HGSC samples using the in vitro organoid bioassay. Fifteen samples were chemotherapy-naïve, 1 was recurrent and platinum-sensitive, 5 were platinum-resistant, and 2 received neoadjuvant treatment.
Flow cytometry detected no surviving cells and cells did not grow when passaged after treatment in 13 samples, indicating sensitivity to the combination. sensitive. Researchers determined that the remaining samples were resistant because of >1% cell survival and robust growth upon passaging. Monotherapy did not have any effect on HGSCs.
La V, Fujikawa R, Janzen DM, et al. Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy [published online April 3, 2017]. npj Precision Oncology. doi: 10.1038/s41698-017-0008-z.