A team of researchers at the University of Alberta has identified a promising new target for treating ovarian cancer, a disease expected to claim the lives of 2,000 Canadian women this year, according to the Canadian Cancer Society.
Ovarian cancer, often referred to as the “silent killer,” is one of the deadliest cancers affecting women due to its lack of early symptoms and late-stage diagnosis. It has one of the lowest survival rates of gynecologic cancers, with many cases going undetected until the cancer has spread beyond the ovaries.
The research team focused on a gene called ZIC2, which is associated with poor survival rates in ovarian cancer patients. Their findings could pave the way for new treatment strategies for this aggressive disease.
Led by YangXin Fu, associate professor of experimental oncology and obstetrics and gynecology, the team is the first to comprehensively investigate the elevated levels of the ZIC2 gene in ovarian cancer cells. Normally, ZIC2 is only active during brain development in embryos and remains inactive in most adults. However, in ovarian cancer, the gene becomes reactivated, driving the growth of aggressive tumours.
“Currently, there’s no effective treatment for ovarian cancer,” says YangXin Fu, associate professor of experimental oncology and adjunct associate professor of obstetrics and gynecology at the U of A. “Also, ovarian cancer cases are often diagnosed at a late stage and by that time, even with surgery and chemotherapy, the cancer recurs and becomes resistant to chemotherapy.
“That is why we need to find a new treatment.”
To explore ZIC2’s role in ovarian cancer, the team used human ovarian cancer cell lines in lab tests and employed CRISPR technology to inactivate the ZIC2 gene. They found that cancer cells with deactivated ZIC2 grew more slowly, migrated less, and formed fewer and smaller colonies. The team then repeated the experiments in mice and observed similar results – tumours where ZIC2 was inactivated grew at a significantly slower rate.
“When we inactivate ZIC2 in those cancer cells, they become less aggressive and form smaller tumours in mice,” says Fu, who is also a member of the . “Of course, it’s a huge step to go from animal work to a clinical trial in humans, but it shows that in the future, if we can find a way to inhibit ZIC2 function, it might reduce tumour formation and progression and provide an effective treatment.”
ZIC2 functions as a transcription factor, or “master regulator,” meaning it controls the activation of other genes. ZIC2 is rarely expressed, or activated, in adults outside of ovarian cancer tissue, making it a safer target for therapy. Interestingly, the team found that when ZIC2 was added to ovarian cancer cells that didn’t naturally express it, tumor growth did not increase, indicating that ZIC2’s effect is highly context-specific.
The next phase of the research will focus on finding ways to inactivate ZIC2 in human patients, as CRISPR technology is not yet approved for human treatments. The team plans to explore small-molecule drugs that could inhibit ZIC2’s function and will investigate new approaches, such as proteolysis targeting chimera (PROTAC), a technique capable of removing unwanted proteins from cells.
This cross-disciplinary effort could lead to significant breakthroughs in the fight against ovarian cancer, offering hope for more effective treatments and improved survival rates.
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