Carboplatin plus birinapant effective against high-grade serious ovarian cancer.
A majority of patients experience a recurrence of high-grade serious ovarian cancer, even after standard treatment with carboplatin. This occurrence has long puzzled researchers.
Preclinical findings may have determined a main driver behind high recurrence, which led to a targeted combination therapy that may be effective in up to 50% of patients with ovarian cancer, according to a study published by Precision Oncology.
The authors discovered that carboplatin plus birinapant, an experimental drug, significantly improved survival in mouse models of ovarian cancer. They also found that testing for a certain protein could identify which patients would benefit from the drugs.
This combination treatment may also effectively target cancer in the bladder, cervix, colon, and lungs, according to the study.
In earlier studies, the authors found that some patients have carboplatin-resistant ovarian cancer stem cells. These stem cells contain a high level of cIAP proteins, which prevent chemotherapy-related cell death. Since these stem cells survive chemotherapy, they are able to regenerate the disease. For ovarian cancer, each recurrence lessens treatment options.
The investigators found that birinapant — which degrades the protein – increases the efficacy of carboplatin in some patients with ovarian cancer.
"I've been treating women with ovarian cancer for about two decades and have seen firsthand that ovarian cancer treatment options are not always as effective as they should be," said researcher Sanaz Memarzadeh, MD, PhD. "Our previous research was promising, but we still had questions about what percentage of tumors could be targeted with the birinapant and carboplatin combination therapy, and whether this combination could improve overall survival by eradicating chemotherapy-resistant ovarian cancer tumors."
In the new study, the authors set out to determine whether birinapant could improve survival in mice models, half of which had carboplatin-resistant ovarian cancer. The mice received treatment with birinapant monotherapy, carboplatin monotherapy, or a combination of the 2 drugs.
Alone, neither drug was observed to have a significant effect, but the combination therapy doubled overall survival in 50% of the mice, regardless of whether their tumors were sensitive or resistant to chemotherapy, according to the study.
"Our results suggest that the treatment is applicable in some, but not all, tumors," said co-first study author Rachel Fujikawa.
The investigators then tested the efficacy of the combination therapy in 23 high-grade serious ovarian cancers from patients, some of whom were treatment-naïve, while others had chemotherapy-resistant disease.
With the patient samples, the authors created ovarian cancers in a laboratory setting and tested the drugs. Their findings were confirmed — the combination of drugs had a significantly better effect than either drug alone. These drugs worked for patients with drug-sensitive and drug-resistant disease.
Next, the authors measured cIAPs in the tumors and found a strong link between high levels of cancer stem cells with the protein and response to combination therapy, according to the study.
Since high levels of the protein have been linked to chemotherapy resistance in other cancers, the authors speculated that the treatment may be effective in other forms of the disease. They tested their findings in human bladder, cervix, colon, and lung cancer cells, which showed that 50% of the tumors were targeted and high cIAP levels indicated a positive treatment response, according to the study.
"I believe that our research potentially points to a new treatment option. 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," Dr Memarzadeh concluded.