CRISPR used to mimic disease, advancing cancer research

Tuesday, 04 October, 2022

CRISPR used to mimic disease, advancing cancer research

A powerful new genome editing technique is enabling researchers to replicate human diseases with high accuracy, with the potential to revolutionise the drug discovery process for a range of cancers. The technology can activate any gene — including those that have been silenced — allowing new drug targets and causes of drug resistance to be further explored.

Researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) have now leveraged this technology to replicate an aggressive form of lymphoma, which they used to identify a gene responsible for triggering drug resistance to a new blood cancer treatment. Their findings have been published in the journal Nature Communications.

Lymphoma is the most common blood cancer in Australia, with around 6500 Australians diagnosed each year. Double hit lymphoma (DHL) is an aggressive subtype that affects white blood cells called B lymphocytes, or B cells.

The research team was able to enhance a genome editing technology, known as CRISPR activation, to accurately mimic DHL. Project lead Professor Marco Herold said the team focused on DHL as the disease is difficult to treat, in part due to a lack of efficient preclinical modelling.

“Without the ability to model a disease, there are limited opportunities to properly test which drugs will be effective for it in the clinic,” said Herold, who established and now leads one of Australia’s most advanced CRISPR laboratories at WEHI.

“The technology is a game changer for the scientific community and people in the clinic as it allows us to mimic diseases like DHL and properly test drug treatments against them for the first time.

“This is significant when you think of the plethora of human diseases that could be better modelled by using this tool.”

The research has sparked international interest, with the WEHI team working closely with researchers from Nanjing University and Genentech (a member of the Roche Group) to test the anticancer drug known as venetoclax. Venetoclax is based on a WEHI discovery from the late 1980s that a protein called BCL-2 helps cancer cells survive indefinitely.

A1 is a pro-survival protein of the BCL-2 family that is encoded by the BCL2A1 gene. Activation of this gene has been reported in diverse forms of cancer, including leukaemia, lymphoma, melanoma, stomach cancer and breast cancer — but while A1 had been thought to play an important role during cancer progression, PhD student Yexuan Deng said this had until now remained unverified.

“As DHL lymphomas from our model can be killed with venetoclax, we were able to leverage this to prove for the first time that A1 is a major factor in resistance to this drug,” said Deng, who served as first author on the new study.

While cancers are often triggered by switching genes on, researchers have largely only been able to switch them off in previous disease models. Project lead Associate Professor Gemma Kelly said the team was able to engineer drug resistance because their model can activate any gene — even those that have been silenced.

“We used this model’s unprecedented ability to switch on A1, which allowed us to confirm the protein as a resistance driver,” Kelly said.

“Our research will allow for more genes to be activated in other models to better understand cancer drivers and, critically, to determine other causes of drug resistance.”

Co-lead author Dr Sarah Diepstraten said the findings reveal A1 to be a promising drug target for DHL — a discovery that was only made possible because the team was able to create a model for DHL that allowed them to switch on any gene.

“This proves the power of our technology when it comes to modelling human diseases and exploring why drug targets work or fail, on an unmatched level,” she said.

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