A common type of ovarian cancer, high-grade serous ovarian cancer, often responds well to the chemotherapy drug carboplatin; however, it frequently recurs following the treatment. Now, UCLA researchers has discovered that malignant cells that do not produce the protein CA125, which is a biomarker used to test for ovarian cancer, have an increased ability to repair their DNA and resist cell death from the chemotherapy. This allows the cells to elude the drug and live long enough to regrow the original tumor. The results of the five-year study were published on August 3 in the peer-reviewed journal Nature Communications.
First author Deanna Janzen, PhD explained that the regenerative ability resistance to carboplatin therapy make ovarian cancer cells so dangerous, She and her colleagues found that pairing the chemotherapy with an experimental drug eliminates the deadly cells believed to be responsible for repopulating the tumor. The drug, birinapant, sensitizes the CA125-negative cells to the chemotherapy by restoring apoptosis (programmed cell death), explained senior author Sanaz Memarzadeh, MD, a UCLA gynecologic cancer surgeon.
The research team found that, compared to using either treatment alone, the combination of chemotherapy and birinapant significantly improved disease-free survival in laboratory models of human ovarian cancer. Dr. Memarzadeh explained that this suggests that targeting the CA125-negative cells may improve outcomes in these high-grade serous cancers, which are the most common subtype of ovarian cancer. She added that this is vital because the cancer recurs in 80-85% of patients despite standard treatments.
The investigators previously theorized that there was a population of cells, which could not be attacked by the use of conventional treatment of surgery followed by chemotherapy; however, they were unable to clearly identify them. “We found that these cells were like little time bombs, hiding from the chemotherapy and then later initiating tumor growth,” noted Dr. Memarzadeh. She added, “We think that by isolating the CA125-negative tumor cells we have uncovered this reservoir of carboplatin-resistant high-grade serous ovarian cancer cells.”
For the study, the researchers first analyzed ovarian tumors from UCLA patients. Most of the cells that comprised the tumors were positive for CA125; however, the researchers found a small population that were negative and focused on them. They wondered if the CA125-negative cells grew the same way as those that were CA125-positive. The results were astonishing. “The CA125-negative cells grew 700 times better than CA125-positive cells,” Dr. Janzen said. She added, “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. She said, “For me, as a physician, this was frightening. 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 measures CA125 levels. Dr. Memarzadeh explained that as a result, the test completely overlooks the cells that slowly regrow the tumor, which are CA125-negative.
Once the research team had isolated the CA125-negative cells, they collaborated with other UCLA researchers 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 located the cells’ “anti-death” protein. The DNA damage that killed the CA125-positive cells did not affect the CA125-negative cells because of the two protective mechanisms.
“These cells reacted like hair does to chemotherapy,” explained Dr. Janzen said. She added, “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 re-growth 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.”
The research team next plans to conduct a clinical trial of the combination therapy in women whose tumors have high levels of the anti-death protein. They estimate that about 50% of women with ovarian cancer have malignancies with this type of tumor and would qualify for the trial, which needs about $2 million in philanthropic funding before it could begin.
The investigators are also searching for other potential drug targets in the 50% of patients who do not have high levels of the anti-death protein, as well as biomarkers in addition to CA125 that could be used to screen for ovarian cancer. “We do a phenomenal job with surgery, peeling off as much of the tumor as we can see, and then we do standard chemotherapy, but the cancers still recur,” noted Dr. Memarzadeh. She added, “I think our study helps explain why this happens. If this combination of drugs proves effective, we may be able to improve outcomes for this deadly disease. I think it’s entirely feasible.”
Ovarian cancer causes 5% of cancer deaths among women, and causes more deaths than any other gynecologic cancer. About 21,000 American women will be diagnosed with ovarian cancer this year, and more than 14,000 will die of the disease.
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