|Ovarian-cancer tumors with higher percentages of cIAP-expressing cells (red) were more sensitive to a potential combination therapy than tumor cells without cIAP-expressing cells.
Graphic: Courtesy of UCLA Broad Stem Cell Research Center/Precision Oncology
Researchers have been trying to understand why up to 85 percent of women experience recurrence of high-grade serous ovarian cancer — the most common subtype of ovarian cancer — after standard treatment with the chemotherapy-drug carboplatin. Preclinical research from Sanaz Memarzadeh, MD (RES ’00, FEL ’03), PhD, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and director of the G.O. Discovery Lab, has potentially solved this mystery and pinpointed a combination therapy that may be effective for up to 50 percent of women with ovarian cancer.
Dr. Memarzadeh’s research shows a combination therapy of carboplatin and an experimental drug called birinapant can improve survival in mice with ovarian-cancer tumors. Additional findings reveal that testing for a specific protein could identify ovarian tumors for which the treatment could be effective. The treatment also could target cancers that affect other parts of the body, including the bladder, cervix, colon and lung.
The team first tested if the combination therapy could improve survival in mice. Half of the mice tested had carboplatin-resistant human ovarian-cancer tumors and the other half had carboplatin-sensitive tumors. The team administered birinapant or carboplatin as well as the two drugs combined and then monitored the mice over time. While birinapant or carboplatin alone had minimal effect, the combination therapy doubled overall survival in half of the mice, regardless of whether or not they had carboplatin-resistant or carboplatin-sensitive tumors.
To assess the combination therapy’s rate of effectiveness in tumors, the team went on to test 23 high-grade serous ovarian-cancer tumors from independent patients. Some were from patients who had never been treated with carboplatin, and some were from patients who had carboplatin-resistant cancer. With these samples, the researchers generated ovarian-cancer tumors utilizing a method called disease-in-a-dish modeling and tested the same treatments previously tested in mice. Once again, carboplatin or birinapant alone had some effect, while the combination of birinapant and carboplatin successfully eliminated the ovarian-cancer tumors in approximately 50 percent of samples. However, the combination therapy worked for both carboplatin-resistant and carboplatin-sensitive tumors.
The researchers also measured cIAPs, which prevent cell death after chemotherapy and are the target for the drug birinapant, in the tumors. They found a strong correlation between cancer stem cells with high levels of cIAP and a positive response to the combination therapy. Since elevated levels of cIAPs have been linked to chemotherapy resistance in other cancers, the researchers wondered if the combination therapy could effectively target those cancers as well.
The team created disease-in-a-dish models using human bladder-, cervix-, colon- and lung-cancer cells and tested the combination therapy. Similar to the ovarian-cancer findings, 50 percent of the tumors were effectively targeted, and high cIAP levels correlated with a positive response to the combination therapy. Dr. Memarzadeh believes the research potentially points to a new treatment option. She hopes to initiate a phase 1/2 clinical trial.
“Birinapant Sensitizes Platinum-resistant Carcinomas with High Levels of cIAP to Carboplatin Therapy,” Precision Oncology, April 3, 2017