Customising liver cancer treatment

NUS researchers from the Yong Loo Lin School of Medicine (NUS Medicine), Faculty of Engineering (NUS Engineering) and Cancer Science Institute of Singapore (CSI), in collaboration with the National Cancer Centre Singapore, have devised an innovative technique to grow in the laboratory liver cancer cells that were derived from patients, paving the way for a more cost effective and efficient method of testing drug efficacy.

This multidisciplinary effort was led by Dr Eliza Fong from NUS Biomedical Engineering and CSI Research Fellow Dr Toh Tan Boon. The research was published online in Biomaterials in January.

Liver cancer is a leading cause of cancer death for both men and women in Singapore, and the disease is often only detected at an advanced stage that is beyond cure. Researchers currently test the efficacy of drugs on models of tumours, known as patient-derived xenografts (PDXs). However, these PDXs are expensive and time-consuming when used for drug screening.

Furthermore, current liver cancer models typically make use of cancer cell lines in which cells are mostly homogeneous or similar. In reality, liver tumours exhibit intra-tumoural heterogeneity in which a single tumour mass can contain multiple distinct populations of cancer cells. “Not all cancer cells within the same tumour are the same. This makes treating liver cancer very challenging; because there is heterogeneity, not all cancer cells may respond similarly to the same drug. This may result in drug resistance later on in the patient,” Dr Fong explained.

This is a major advancement for liver cancer because researchers, for the most part, have not been able to achieve a reliable method of culturing primary liver cancer cells in a drug screenable platform outside of the body.

The researchers grew cancer cells from 14 liver cancer PDXs, each line derived from a patient with liver cancer, on an engineered three-dimensional (3D) scaffold fabricated from a plant-based porous hydrogel that mimics the cellular environment in the liver. The spongy scaffolds, measuring 6mm in diameter, serve as housing for the cancer cells and were designed to have optimised biochemical and mechanical properties conducive for the culture of liver cells. These properties allow the cells to preserve their shape and function and grow as organoids.

The 3D organoids possess several advantages over existing liver cancer models. Not only are they able to replicate the intra-tumoural heterogeneity found in liver tumours as well as molecular profile, they are minuscule in size — a mere 0.1mm. Through this technology, one PDX can be used to produce up to hundreds of scaffolds containing organoids for drug studies, increasing the throughput for drug screening.

Speaking of the impact of the research, Professor Hanry Yu from NUS Physiology and Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research, said, “The spongy scaffolds were developed to keep normal liver cells happy and also preserve the important properties of liver cancer for drug testing. This could one day allow patients to choose the best treatment based on the drug testing results of their own liver cancer cells.”


Hepatocellular carcinoma organoids in culture

Dr Toh said that time is a crucial factor in treating liver cancer patients. “Our goal is to move towards personalising treatment for individual patients. If we can screen for drugs that actually work, patients may have a better chance of getting the right treatment,” he said. Dr Fong added that with this platform, it may be possible to derive drug responses on patient tumours in one to two weeks.

Elaborating on the work, Assistant Professor Edward Chow from NUS Pharmacology and CSI said, “This is a major advancement for liver cancer because researchers, for the most part, have not been able to achieve a reliable method of culturing primary liver cancer cells in a drug screenable platform outside of the body.”

The research team aims to build a more complex liver cancer model to better mimic the disease in patients by including other tumour supporting cells such as immune cells and blood vessels.

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