Research unlocks potential new treatments for rare type of cancer

A Dundee family afflicted with an extremely rare form of cancer may benefit from new research initiated by a University of Dundee clinical academic. 

Since 2014 Dr Anil Mehta, from the University’s School of Medicine, has worked closely with the Williamson family of Dundee to understand more about a gene mutation that causes a rare form of cancer found in generations of the family. 

The Williamson family carries a faulty SDHB gene, a gene that normally codes for a major component in the energy production system of the body that is located in mitochondria, otherwise known as the powerhouses of the cell. Most cancer-causing genes are concerned with regulation of cell division, cancer secondary to energy supply genes is a rare exception. 

The faulty SDHB gene, known as the Arg230His mutation, makes some members of the family susceptible to tumours which can be aggressively malignant. The tumours in this condition, pheochromocytoma and paraganglioma, arise in nerve cells which are often concerned with the control of hormones related to the flight or fight response of the adrenal glands. 

Dr Mehta, whose primary work focuses on research concerning cystic fibrosis, asked his existing consortium of researchers to switch their focus to study how the faulty SDHB gene works. 

For the first time, using worms, the researchers have successfully made a biological ‘model’ of the SDHB Arg230His mutation, providing a platform for investigation and testing of the biological effects of the exact gene change seen in the Williamson family. 

Dr Mehta, Honorary Reader and Honorary Consultant Paediatrician, said, “To find out what was going on, we exploited the fact that this gene has remained unchanged over Millennia. 

“We looked for an animal that was amenable to genetic manipulation and whose cell structure and development from embryo to adult was fully characterised. This led us to the worm, an elegant millimetre sized worm called Caenorhabditis elegans, which has been responsible for so much understanding in cancer biology. 

“We recreated the Williamson mutation in the worm and found that this worm not only lives a shortened life span but also shows a delayed and very abnormal development characteristic of known pathways linked to cancer.   

“Our findings show that the gene change alters the pattern of energy production. The burn of the sugar into hydrogen still happens in members of this family with the cancer of the nerves but the route of burning differs because the sugar is not fully used.   

“In short, the Williamson worm makes far too much lactic acid. When we block the production of this lactic acid with drugs, we can kill these worms. Thus, we have the possibility of screening these mutant worms with drug cocktails, looking for drug candidates that might kill the worms and in turn find drugs that might also kill the cancers found in the family.” 

In 2018 the Williamson family set up the Phaeo and Para Cancer Charity to raise funds in the aim of supporting further research on the faulty gene. 

The charity is now working on tumours removed from affected members of the family to look for overlapping abnormalities between the cancer genes in the tumours and the findings from the Williamson worm genes. This work is being done with a local company called MicroMatrices and is being led by Dr Simon Plummer. 

The research was undertaken by a consortium of scientists from Hungary, Singapore and India. The findings are published online on The Company of Biologists site.