Researchers at the University of Basel have established a collection of 35 patient-derived mini-tumours to test potential drug combinations for hepatocellular carcinoma, the most prevalent form of liver cancer. According to published findings in Cell Reports, the living three-dimensional structures replicate key biological traits of the original cancers, allowing laboratory teams to evaluate how diverse tumours respond to targeted therapies despite considerable patient-to-patient variation.
Screening 1,600 Compounds Across Advanced Biopsies
Liver tumours frequently resist standard therapies because their biology changes depending on the underlying cause of the disease and specific genetic mutations within the cancer cells. To capture this complexity, the Basel research team screened 1,642 compounds across an initial set of four carefully chosen organoid lines. The tested compounds spanned existing cancer drugs, experimental agents, and medications already approved for unrelated conditions.
What distinguishes this collection from previous organoid models is its inclusion of advanced tumours. Many of the mini-tumours originated from small tissue samples gathered during diagnostic needle biopsies, meaning late-stage cancers are well represented rather than underrepresented. “Our collection reflects different stages of the disease, as well as liver tumors with various causes,” stated Sandro Nuciforo, the study’s first author and project leader at the University of Basel.
Did you know? Traditional cancer models often struggle to capture late-stage heterogeneity, whereas needle-biopsy organoids preserve the distinct biological characteristics of advanced patient tumours.
Targeting Multiple Vulnerabilities With Drug Combinations
After identifying the most potent anti-tumour compounds from the initial library screening, the team shifted focus toward multi-drug therapies. Rather than targeting a single tumour vulnerability, researchers combined agents with different mechanisms of action to maintain efficacy across biologically diverse samples.
“Rather than focusing on a single vulnerability of the tumour, we combine drugs with different mechanisms of action,” said Dr. Markus Heim, research group leader at the University of Basel. “This could allow the treatment to remain effective even when the vulnerabilities differ from tumour to tumour.”
According to the published study, certain two- and three-drug combinations outperformed individual treatments across multiple tumour organoids. Furthermore, specific three-drug combinations exhibited a markedly weaker effect on non-tumour liver organoids than on the cancer models, indicating a higher degree of cellular selectivity.
Efficacy Tests in Animal Models
The research team selected one specific triple-drug regimen for advanced evaluation: a combination of regorafenib, selinexor, and ixazomib. When tested in mice carrying tumours derived from patient organoids, the three-drug therapy slowed tumour growth more effectively than regorafenib administered on its own, according to the study data.
Importantly, the combination produced no significant additional toxicity within the tested animal model. However, researchers emphasize that clinical application in human patients remains distant. Organoids and animal models cannot yet fully replicate the intricate microenvironment of a human tumour, which includes blood vessels, immune cells, and supporting tissues. Additional studies must clear these preclinical hurdles before clinical trials can begin.
Frequently Asked Questions
What is a liver cancer organoid?
An organoid is a three-dimensional structure grown from living cancer cells extracted from patient tissue. These mini-tumours retain the key genetic and biological characteristics of the original cancer.
Why are liver tumours difficult to treat?
Liver tumours vary considerably from one patient to another based on the disease’s underlying cause and distinct cellular mutations, causing patients to respond very differently to standard drugs.
Can these drug combinations be used in patients now?
Keep reading