Birinapant in Combination With Carboplatin May Be Effective Against Serous Ovarian Cancer
High-grade serous ovarian cancer often responds well to the chemotherapy drug carboplatin, but it frequently recurs after the first line of treatment. A team of University of California, Los Angeles, researchers has discovered that a subset of tumor cells that don’t produce the protein CA125, a biomarker used to test for ovarian cancer, has an enhanced ability to repair DNA and resist programmed cell death, which allows the cells to evade the drug and live long enough to regrow the original tumor.
That regenerative ability and the resistance to carboplatin therapy is what makes the cells so dangerous, said Deanna Janzen, PhD, a senior scientist in the G.O. Discovery Lab at UCLA.
Birinapant Combination
The study, published by Janzen et al in Nature Communications, showed that pairing the chemotherapy with an experimental drug eliminates the deadly population of cells believed to be responsible for repopulating the tumor.
The drug, birinapant, sensitizes the CA125-negative cells to the chemotherapy by restoring apoptosis, said Sanaz Memarzadeh, MD, PhD, Gynecologic Cancer Surgeon, Director of the G.O. Discovery Lab, and Associate Professor of Obstetrics and Gynecology.
Combining chemotherapy and birinapant significantly improved disease-free survival in laboratory models of human ovarian cancer compared to using either therapy alone. This suggests that targeting the CA125-negative cells may improve outcomes in these high-grade serous cancers, the most common subtype of ovarian cancer, said Dr. Memarzadeh. This is vital, since the cancer recurs in 80% to 85% of patients, despite standard treatments.
Scientists had previously hypothesized that there was a population of cells that could not be reached using the conventional treatment of surgery followed by chemotherapy, but they had been mostly unable to identify them.
“We found that these cells were like little time bombs, hiding from the chemotherapy and then later initiating tumor growth,” Dr. Memarzadeh said. “We think that by isolating the CA125-negative tumor cells, we have uncovered this reservoir of carboplatin-resistant high-grade serous ovarian cancer cells.”
CA125-Negative Cell Properties
In the 5-year study, the research team first analyzed ovarian tumors gathered from patients at UCLA. Most of the cells that made up the tumors were positive for CA125, but the researchers found a small population that were negative and focused on those. The team wondered if the CA125-negative cells grew the same as those that were CA125-positive.
“The CA125-negative cells grew 700 times better than CA125-positive cells,” Dr. Janzen said. “It was very striking that the two cell populations had such different growth potentials. But what was more remarkable was that the CA125-negative cells were clearly resistant to the drugs normally used to treat serous cancers.”
Dr. Memarzadeh agreed. “For me, as a physician, this was frightening,” she said. “The chemotherapy drug killed the CA125-positive cells and left behind the cells armed with the capacity to regrow the tumor.”
The test most widely used to detect recurrences of serous cancer works by measuring CA125 levels. As a result, Dr. Memarzadeh said, the test completely overlooks the cells that slowly regrow the tumor, which are CA125-negative.
Once the researchers isolated the CA125-negative cells, they worked with UCLA collaborators to analyze the genes expressed in these cells. They discovered the ability of these cells to quickly repair the DNA damage done by the chemotherapy, and they found the cells’ “antideath” protein. The DNA damage that killed the CA125-positive cells did not work on the CA125-negative cells because of the two protective mechanisms.
“These cells reacted like hair does to chemotherapy,” Dr. Janzen said. “The treatment damages most of patients' hair cells, causing the hair to fall out. But the cells responsible for hair growth live on, so hair regrows after therapy stops. Similarly, most of the tumor cells die in response to platinum therapy, but the CA125-negative cells survive and serve as a source of tumor regrowth once therapy ceases. The good news is that we found a small-molecule drug being tested in cancers that activates apoptosis, and we decided to test it in combination therapy.”
Future Studies
Going forward, Dr. Memarzadeh and her team plan to conduct a clinical trial of the combination therapy in women whose tumors have high levels of the antideath protein. She estimates that about 50% of women with ovarian cancer have tumors with this type of tumor and would qualify for the trial.
The researchers also are seeking other potential drug targets in the 50% of patients who don't have high levels of the antideath protein, as well as biomarkers in addition to CA125 that could be used to screen for ovarian cancer.
Dr. Memarzadeh is the corresponding author for the Nature Communications article.
The study was supported by the American Cancer Society, the Ovarian Cancer Circle Inspired by Robin Babbini, the Leath L. and Marcia L. Millen Family Fund, the Phase One Foundation, the Lynn Cohen and the Gynecologic Oncology Discovery Lab Foundations, the National Cancer Institute, the Veterans Affairs Career Development Program, the National Institutes of Health/National Center for Advancing Translational Science UCLA Clinical Translational Science Institute, and the Jonsson Cancer Center Foundation at UCLA.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
