Genetic Signature Presents New Ovarian Cancer Drug Target

A recent study identified a gene signature that predicts poor survival for patients with ovarian cancer, as well as the identification of genes that promote cancer treatment resistance.

It’s been shown that the HOX gene family enables rapid cell division in developing embryos; however, most of these genes are switched off in adults. Prior research has shown that the HOX genes are switched back on in some cancers, including ovarian cancer, and helps cancer cells proliferate and survive.

In a study published in the International Journal of Cancer, researchers analyzed tissue samples from 99 women with epithelial ovarian cancer (EOC), and compared them with healthy ovarian and fallopian tube tissue samples. The results of the study showed there was little to no HOX expression found in normal ovarian tissue.

However, 36 of the 39 HOX genes were found at high levels in tissue samples of the EOC subtype called high grade serous, which accounts for about 80% of epithelial ovarian cancers.

Researchers also found a strong 5-gene signature in all patients who died from the disease, regardless of their length of survival.

Additionally, extensive tests were conducted on cells and preliminary tests on mice using the peptide drug HXR9, which targets HOX by blocking the function of the proteins the gene expresses, forcing cancer cells to die. Researchers tested both HXR9 and cisplatin, a drug commonly used to treat ovarian cancer, as well as a combination of the 2 drugs.

They found that when the drugs were combined, it significantly increased the number of cancerous cells that were killed compared with either of the drugs used alone.

“We’ve identified a set of genes which play a contributing role in resistance to chemotherapy, which is a major problem in the treatment of ovarian cancer,” said study co-author Zoe Kelly. “We also have strong and extensive cell line data which shows that using HXR9 can overcome this drug resistance, making the cell more susceptible to chemotherapy treatment.

“The results in mice were encouraging, but more muted: treated mice survived for longer, but the cell killing of the combination approach was only marginally better than HXR9 used on its own,” Kelly continued. “However, these tests were carried out over a very short timeframe, and I believe that more extensive tests in the mouse model would show clearer results. This needs to be the next step for this research.”

The findings suggest that this approach could help prevent chemotherapy resistance from developing and provide an alternative route for the treatment of ovarian cancer.

“This is the first comprehensive analysis of HOX gene expression in ovarian cancer and the first study to analyze changes in HOX expression in resistant cancer cells,” said lead researcher Richard Morgan. “The results strongly suggest that targeting these genes as a new treatment approach warrants further investigation. It also supports our belief that HXR9 should be further developed and tested in clinical trials.”