Perkins researchers have led a major collaborative study exploring a new way to switch off a key genetic driver of Ewing sarcoma, an aggressive cancer that mostly affects children and young people.
Recently published in Molecular Therapy, the research brought together multiple teams from across the Perkins, The University of Western Australia and national and international collaborators.
Around 85 per cent of Ewing sarcomas are driven by an abnormal joining of two genes, known as EWSR1-FLI1. This fusion produces a cancer-promoting protein that then changes the activity of other genes and ultimately drives tumour growth.
Rather than trying to develop a drug against the resulting protein, the team investigated whether they could effectively switch off the cancer-causing gene itself and stop the tumour growth at the root cause.
The researchers used an adapted form of CRISPR technology called dCas9-KRAB to go closer to the source and effectively ‘switch off’ the cancer-driving gene.
This version of CRISPR does not cut or permanently change the DNA, like traditional CRISPR. Instead, it’s programmed to find a specific genetic target and silence its activity.
The team also developed a non-viral delivery system to transport the gene editing machinery into cancer cells.
In preclinical models of Ewing sarcoma, including models developed from patient tumours, the approach successfully reduced the activity of EWSR1-FLI1 and produced strong anti-cancer effects.
Professor Pilar Blancafort, Head of the Cancer Epigenetics Laboratory at the Perkins and senior author of the study, said the approach could offer a new way to tackle some of cancer’s hardest targets.
“Some of the genes that are most important in driving cancer are also among the hardest to target with existing medicines. Our approach is designed to go closer to the source and selectively switch off the cancer-driving gene.”
Importantly, this is the first preclinical study to successfully deliver the molecular components of CRISPR into a patient-derived sarcoma model. Delivering CRISPR safely and effectively has been a major challenge in moving the technology towards clinical use.
“By showing that CRISPR can be delivered into advanced sarcoma models and silence the gene driving the cancer, this research provides an important step towards the future development of CRISPR-based treatments,” Professor Blancafort said.
While the research focused on Ewing sarcoma, the technology could potentially be adapted to target other difficult-to-treat cancer-driving genes.
Read the paper: Targeting of the oncogenic fusion EWSR1-FLI1 in Ewing sarcoma by CRISPR/dCas9 silencers, published in Molecular Therapy.
