Development of biomarkers to predict the development of secondary brain tumours
Mitochondria are responsible for the provision of energy within cells. Cancer cells, including brain tumour cells, have a greater energy requirement as they are constantly growing and dividing. Previous studies have suggested that the mitochondria in tumour cells may be more efficient than those in non-cancer cells. So, new therapies which would dampen down the energy that is produced within the cell could therefore slow down, or halt, the growth of a tumour. In order to develop these, we need to understand any potential changes that occur within the mitochondria in cancer cells. Studies carried out at our Research Centre at the University of Portsmouth have been working to better understand potential changes in the mitochondria in cancer cells and how best we can use this information to ultimately develop new therapies.
While the majority of our genetic material (DNA) is contained in the chromosomes located within the nucleus of a cell, the mitochondria also have a certain amount of their own genetic material which contributes towards their development and maintenance. This plays a key role in determining how active they are.
In addition to primary tumours which start in the brain, secondary tumours originate elsewhere and subsequently migrate to the brain. These are also referred to as metastatic tumours. Secondary brain tumours are most likely to originate in the breast or lung. When they enter the brain, they may form multiple tumours and can be extremely difficult to treat. Usually, this would require whole-brain radiation which is extremely toxic and the average survival time is just 3–6 months from diagnosis, with fewer than 20% of patients surviving more than one year. So, if the people whose tumours are more likely to spread to the brain could be identified, we may be able to prevent this from happening.
Biomarkers are potential tools which may provide an indication of whether somebody has a tumour, what stage it is at or whether it is more likely to respond to specific therapies. Ideally, these could be assessed as part of a blood test. Members of our research centre in Portsmouth have been combining their knowledge on mitochondria to answer a question. Is it possible to measure mitochondrial DNA in the blood and, if so, could this tell us which cells are more likely to form secondary brain tumours? If so, we may be able to prevent the circulating tumour cells from entering the brain as well as identifying people with a greater likelihood of developing secondary tumours.This study examined blood samples from 13 women with early stage breast cancer who subsequently went on to develop secondary brain tumours. Although there are a lot of differences between the individual patients, the researchers identified similar changes in the DNA of three of the patients that code mitochondria energy producing proteins. The authors have used computer programmes to build up 3-dimensional models of the protein structures and how they may look and the evidence suggests that these changes in structure will influence the efficiency of the mitochondria.
Although the changes were only identified in a proportion of the patients studied, the researchers have proposed that this may be one way of developing markers to identify whether people are more likely to get secondary tumours. This could potentially allow for early treatment in order to kill the circulating cancer cells before they reach the brain. The information will also increase our understanding about changes that may occur in mitochondria in other tumour cells, including primary brain tumours, and therefore help to bring us closer to developing new and more effective therapies.
McGeehan RE, Cockram LA, Littlewood TJ, Keatley K, Eccles DM, An Q (2017). Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples. Mitochondrial DNA (Part A). In press