Peptide drug could treat liver cancer more effectively

An international team of scientists, led by the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore, has developed a novel peptide drug called FFW that could potentially stop the development of hepatocellular carcinoma (HCC), or primary liver cancer.

HCC is a fast-growing cancer of the liver, with patients typically surviving for only 11 months after diagnosis. It accounts for over 90% of all liver cancers and poses a major public health problem in the Asia–Pacific region.

The main first-line treatment for HCC is the drug Sorafenib, which has adverse side effects and prolongs survival for only three months. The lack of effective treatment alternatives, coupled with late discovery, has led to HCC becoming the second-leading cause of cancer deaths worldwide.

SALL4 — a protein related to tumour growth — has meanwhile been widely studied as a prognosis marker and drug target for HCC and other cancers such as lung cancer and leukaemia. It is usually present in the growing foetus but is inactive in adult tissue.

In cancers such as HCC, however, SALL4 is reactivated, associating with the protein nucleosome remodelling deacetylase (NuRD) to silence tumour-suppressor genes, such as PTEN. According to Professor Daniel Tenen, Director of CSI Singapore, this protein partnership is “crucial for the development of cancers such as HCC”.

The problem is, SALL4 has previously been classified as an ‘undruggable target’. This is because drug molecules which act on protein interactions like SALL4-NuRD often require the target proteins to have a small ‘pocket’ in their 3D structure where the drug molecule can reside and take effect.

“Instead of looking for ‘pockets’ on SALL4, our research team designed a biomolecule to block the interaction between SALL4 and NuRD,” said Prof Tenen, whose work has been published in the Proceedings of the National Academy of Sciences. “In our lab experiments, blocking this interaction has led to tumour cell death and reduced movement of tumour cells.”

Utilising a creative integrated approach, combined with structural analysis techniques, the researchers’ efforts led to the design of the peptide FFW, which is a small chain of amino acids that can interfere with SALL4-NuRD interactions. FFW could effectively block the huge protein-protein interaction surface and does not require a ‘pocket’ to take effect.

The research team also discovered that FFW, when used in combination with Sorafenib, could reduce the growth of Sorafenib-resistant HCC. While most targeted therapies are small-molecule drugs, a well-designed peptide drug — such as FFW — tends to possess higher selectivity over large binding surfaces with a safer toxicity profile compared with small molecules.

The targeting of the SALL4-NuRD interaction as a cancer-cell-specific target represents an exciting avenue for the development of therapeutic options — one that the research team is keen to pursue.

“An ideal cancer target should be cancer-specific and non-toxic to normal tissues,” noted Associate Professor Li Chai from Brigham and Women’s Hospital at Harvard Medical School. “To this end, we are collaborating to find a missing link that can cure cancer and restore normal cell function.”

“Based on the information we gained from structural and global gene expression, we are continuing our work on this peptide and other peptides with similar structures, with the aim of eventually being able to make them into clinical-grade drugs for the benefit of patients,” added Dr Liu Bee Hui, Research Fellow at CSI Singapore.

Prof Tenen said the team’s discovery has “important implications for treatment of HCC”, noting that their work “could also be beneficial to a broad range of solid cancers and leukaemic malignancies with elevated SALL4”.

“In our latest work, the research team has also demonstrated an effective strategy to accurately target oncogenes previously considered undruggable,” he said. “Moving forward, we hope to investigate how the targeting of these protein interactions might pan out in other cancer types.”

Image caption: Professor Daniel Tenen (right) and Dr Liu Bee Hui (left) are members of the research team whose novel peptide drug could potentially treat liver cancer more effectively. Image credit: National University of Singapore.