Potential new drug targets for an aggressive type of brain tumour have been uncovered in the lab, thanks to a ‘reverse engineering’ approach using DNA editing.
Scientists from the University of Toronto, the Hospital for Sick Children, and the University of Calgary switched off genes, one by one, in specialised cancer stems cells using the DNA editing tool CRISPR.
The stem cells came from patients with an aggressive type of brain tumour, called glioblastoma.
This early stage research, published in the journal Cell Reports, uncovered multiple weak spots in the lab-grown cells that could be used in the future as potential targets for drug development.
Dr Daniel Tennant, cancer biology expert from the University of Birmingham, said glioma stem cells are rare, aggressive brain tumour cells that could help the disease to return or become resistant to treatment.
“Targeting these stem cells is difficult, as they share a number of characteristics with other important stem cells in the brain,” he said.
Identifying potential drug targets specific to these stem cells could focus research into targeted treatments that might limit damage to healthy cells in the brain.
What is ‘reverse engineering’?
This is the first published study to systematically profile and pin down what makes brain tumour stem cells tick using gene editing technology called CRISPR.
Using CRISPR, the team put the glioblastoma stem cells through ‘cell fitness screens’. The technique uses a pair of molecular ‘scissors’, which precisely snip and switch off target genes in the glioblastoma stem cells one by one, to see which helped the stem cells to survive and grow.
Tennant said the team then “looked for proteins on glioma stem cells which are essential for them to live, but not essential for other stem cell types.”
Even though glioblastoma tumours can look very different from patient to patient, the team found a total of 1,007 active genes in at least 6 out of 10 samples. These findings suggest there are a core set of genes that glioblastoma tumours rely on to survive. The researchers then ranked these target genes in order of importance to study in later drug development projects.
Just the start for making new drugs
Dr Noor Gammoh, a Cancer Research UK-funded brain tumour scientist from the University of Edinburgh, added that while the study is interesting, it’s just the starting point.
“The main question that still haunts glioblastoma research is whether we can develop small molecules that can effectively reach the tumour and stop it growing.”
Tennant added that while this study is only the first step, it has already suggested a significant number of new targets that could be good candidates for further investigation.
“Interestingly, they found proteins that appeared unique for the glioma stem cells, which in one case already has an experimental treatment designed against it,” he said.
Macleod, G. et al (2019) Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells. Cell Reports doi.org/10.1016/j.celrep.2019.03.047