Combination therapy inhibits resistance and recurrence in ovarian cancer

High-grade serous ovarian cancer often responds well to the chemotherapy drug carboplatin, but why it so frequently comes back after treatment has been a medical mystery. Now researchers have discovered that a subset of tumor cells that do not produce the protein CA125, a biomarker used to test for ovarian cancer, has an enhanced ability to repair their DNA and resist programmed cell death. This allows the cells to evade the drug and live long enough to regrow the original tumor.

This regenerative ability and tumor cells' resistance to carboplatin therapy that make them so dangerous, said Deanna Janzen, PhD, the study's first author, and a senior scientist in the G.O. Discovery Lab at University of California Los Angeles (UCLA). The study was published in Nature Communications (2015; doi:10.1038/ncomms8956).

The study showed that pairing the chemotherapy with an experimental drug, birinapant, eliminates the deadly population of cells believed to be responsible for repopulating the tumor.

Birinapant sensitizes the CA125-negative cells to the chemotherapy by restoring apoptosis, said Sanaz Memarzadeh, MD, PhD, a senior author of the study and a UCLA gynecologic cancer surgeon.

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 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," 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."

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, Janzen said. The team wondered if the CA125-negative cells grew the same as those that were CA125-positive. The results were alarming.

"The CA125-negative cells grew 700 times better than CA125-positive cells," 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."

"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."

Going forward, 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 approximately 50% of women with ovarian cancer have tumors with this type of cells and would qualify for the trial, which needs approximately $2 million in philanthropic funding before it could begin.

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