Scientists at Princess Margaret Cancer Centre have identified the drivers of a crucial gene involved in prostate cancer, revealing new targets for drug design.
Researchers identified a set of cis-regulatory elements – namely enhancers and the promoter – in the non-coding region of the genome, which affect the expression of FOXA1 gene, one of the major drivers or oncogenes involved in prostate cancer development.
FOXA1 has long been recognized as playing an important role in malignancy, but it is one of the most challenging targets for drug development in cancer.
Often termed “undruggable,” it is extremely difficult to inhibit due to its lack of easily accessible “pockets” for small molecule therapies to slip into to break the deadly uncontrolled cell growth leading to cancer.
Scientists the world over are looking at different ways to target FOXA1, since it is implicated in many cancers including breast, prostate, lung, thyroid and esophageal squamous cell carcinomas.
“To track a tumour, we also have to look at the non-coding space in its DNA because that’s where gene expression – the switching on or off of a gene – happens,” explains Dr. Mathieu Lupien, Senior Scientist at Princess Margaret Cancer Centre and the senior author of this latest research.
“We can’t dismiss what’s going on in the non-coding space because that is what fuels differences in expression in genes. To fully understand a tumour, we have to explore the whole genome – the genes and the non-coding space.”
Scientists have begun mining the dark or non-coding portion of the genome – about 98 per cent of the genome – as a potential source of new targets for drug development.
Dr. Lupien, who is also an assistant professor with the University of Toronto’s Department of Medical Biophysics, is one of the first researchers to realize that hidden amongst the non-coding DNA are crucial elements that not only control the activity of thousands of genes, but also play a major role in many diseases. Exploring this area could provide important sequencing clues for potential cures.
Dr. Lupien’s current research, entitled “Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer” is published in Nature Communications, Jan. 23.