Although immunotherapies have greatly improved the treatment of liver cancer, they are not effective for all patients.

The problem is that liver tumours can differ substantially in their biology depending on factors such as the cause of the disease and genetic changes in the cancer cells.

Consequently, they can respond very differently to drugs.

A research team led by Professor Markus Heim and Dr. Sandro Nuciforo at the University of Basel now reports on new uses for approved drugs and new drug combinations.

Their results are published in Cell Reports.

One of these combinations proved promising in an animal model.

For their study, the researchers established a collection of 35 organoid lines from the most common form of liver cancer, hepatocellular carcinoma.

These three-dimensional structures are made up of living cancer cells and retain key characteristics of the original tumour.

Such organoid collections are already used to search for new drugs.

What sets the Basel collection apart, however, is that many of these mini-tumours were grown from small tissue samples obtained during diagnostic needle biopsies.

This means the collection includes advanced tumours, which were underrepresented in previous organoid collections.

"Our collection reflects different stages of the disease, as well as liver tumours with various causes," explains Sandro Nuciforo, the study's first author.

This allows us to test which drugs are effective despite the significant biological differences between the tumours.

More than 1,600 compounds screened

In an initial automated screening, the team tested 1,642 compounds on four carefully selected liver cancer organoids.

These included cancer drugs, experimental compounds, and drugs that had been approved for other diseases.

The researchers then tested the most promising compounds on a larger selection of organoids.

Several drugs demonstrated a potent anti-tumour effect and could be considered for use in treating liver cancer.

The researchers then searched specifically for combinations of drugs with different mechanisms of action.

"Rather than focusing on a single vulnerability of the tumour, we combine drugs with different mechanisms of action," says Markus Heim.

"This could allow the treatment to remain effective even when the vulnerabilities differ from tumour to tumour."

Some two- and three-drug combinations were more effective against different tumour organoids than individual drugs were.

However, for some three-drug combinations, the effect was markedly weaker on non-tumour liver organoids than on cancer models, suggesting that tumour cells may be targeted more selectively.

Tests in an animal model

The researchers then examined a particularly promising combination of regorafenib, selinexor, and ixazomib more closely.

In mice with tumours derived from patient organoids, the triple therapy slowed tumour growth more effectively than regorafenib alone and did not exhibit significant additional toxicity in the studied model.

Further studies are needed before it can be used in patients.

For example, organoids only incompletely capture blood vessels, immune cells, and other components of a tumour’s microenvironment.

This study demonstrates how a diverse collection of organoids derived from patient samples can be used to systematically test drugs and develop combination therapies that are effective despite major differences between tumours.

Source: University of Basel