A family of genes called homeobox (HOX), involved in the embryo growth process, may be activated in ovarian cancer, resulting in resistance to chemotherapy and poor prognosis, according to researchers at the University of Surrey in England.
The study, “The prognostic significance of specific HOX gene expression patterns in ovarian cancer,” published in the International Journal of Cancer, also revealed that targeting HOX with a drug known as HXR9 could help prevent chemotherapy resistance.
“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,” the study’s lead author, Dr. Zoe Kelly, said in a press release. “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.”
HOX genes are a family of transcription factors that regulate the expression of genes involved in DNA repair and cell differentiation. Although most of these genes are switched off in adult life, some cancers, including ovarian cancer, can switch their expression back on. However, how their aberrant expression influenced the disease was unclear.
In this study, the team found that all patients who died from this disease had a high level of five specific HOX genes, regardless of their length of survival, revealing that HOX genes are predictors of poor prognosis.
The team analyzed samples from 73 women with epithelial ovarian cancer (EOC) — the most common type — and compared them to those of 10 normal ovarian and three fallopian tube tissue samples. Though little HOX expression was found in normal ovarian tissue, 36 out of the 39 HOX genes were found at high levels in EOC samples. Five of these genes were found to be predictive of poor prognosis.
The researchers then tested whether HXR9 was able to impair the proper functioning of the proteins coded by HOX genes, thereby decreasing cancer progression. They combined HXR9 with cisplatin, the most common drug used to treat ovarian cancer, and tested each drug individually. Importantly, combining both drugs significantly increased tumor cell death and slowed tumor growth in mice, compared to either drug used alone.
“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 said. “However, these tests were carried out over a very short time frame, 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.”
Prof. Richard Morgan, director of the University of Bradford’s Institute of Cancer Therapeutics, who developed HXR9, said this is the first comprehensive analysis of HOX gene expression in ovarian cancer, as well as the first study to analyze changes in HOX expression in resistant cancer cells.
“The results strongly suggest that targeting these genes as a new treatment approach warrants further investigation,” Morgan said. “It also supports our belief that HXR9 should be further developed and tested in clinical trials.”
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