Gene discovered in ovarian cancer cells identified as potential new target for treatment

A University of Alberta research team has discovered a potential new therapeutic target for ovarian cancer. Their new research is the first to comprehensively examine the high expression of a gene called ZIC2 in ovarian cancer cells, find that it is associated with poor survival rates for ovarian cancer patients, and test ways to inactivate the gene.

The research is published in the journal Oncogene.

According to the Canadian Cancer Society, ovarian cancer could kill about 2,000 women in Canada this year. About a quarter of ovarian cancer cases have high levels of the ZIC2 protein in the cancer cells.

The ZIC2 protein is produced by the ZIC2 gene, which is normally responsible for human brain development in the embryonic stage and then remains inactive in adults, except in the brain and testes. It is not understood why the gene is reactivated in ovarian cancer with such deadly consequences.

“There is currently no effective treatment for ovarian cancer,” says YangXin Fu, associate professor of experimental oncology and adjunct associate professor of obstetrics and gynecology. “In addition, ovarian cancer cases are often diagnosed at a late stage, and at that stage, even with surgery and chemotherapy, the cancer comes back and becomes resistant to chemotherapy.”

“That’s why we need to find a new treatment.”

The team began by testing the ZIC2 gene in test tubes, using human ovarian cancer cell lines. They identified those with high expression of the gene and then used CRISPR technology to inactivate it. They found that cancer cells with the inactivated ZIC2 gene grew more slowly, migrated less, and formed fewer and smaller colonies.

They then repeated the experiments by implanting the ovarian cancer cells into mice and observing their behavior. Again, they found a similar slowdown in cancer growth in tumors where the ZIC2 gene had been inactivated.

“When we turn off ZIC2 in these cancer cells, they become less aggressive and form smaller tumors in mice,” Fu says. “Of course, it’s a big step to go from animal work to a human clinical trial, but it shows that in the future, if we can find a way to inhibit the function of ZIC2, it could reduce tumor formation and progression and provide an effective treatment.”

ZIC2 is a transcription factor, meaning it has the ability to turn many other genes on or off, a sort of “master regulator,” Fu says, but it’s rarely expressed in adults except in ovarian cancer tissue, so he thinks it’s safe to target it.

Interestingly, the team tried adding the ZIC2 gene to ovarian cancer cell lines that didn’t naturally express it and found, to their surprise, that it didn’t increase tumor growth. This indicates that ZIC2 treatment is context-specific, Fu says, meaning it should be specific to cells where the gene is already present.

Fu says the next step in the research will be to look for ways to inactivate ZIC2 in human patients, since CRISPR is not yet used for human treatment.

He says the team will look for small molecule drugs that can inhibit gene function and will also explore the proteolysis-targeting chimera or PROTAC approach, which is capable of removing specific unwanted proteins.