A new drug called FFW that could potentially stop the development of hepatocellular carcinoma or primary liver cancer has been developed by scientists at the Cancer Institute of Singapore. The discovery opens the door for more effective treatments with fewer side effects.

Hepatocellular carcinoma (HCC) is a fast-growing cancer of the liver, and patients typically survive 11 months after diagnosis. HCC accounts for over 90 percent 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 multikinase inhibitor 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.

A Previously Undruggable Target

Researchers have widely studied Sal-like 4 (SALL4), a protein related to tumor growth, as a prognosis marker and drug target for HCC and other cancers such as lung cancer and leukemia. It is usually present in the growing fetus but inactive in adult tissue.

In some types of cancer, such as HCC, SALL4 reactivates, leading to the growth of tumors. However, SALL4 has previously been classified as an “undruggable target.”

Drug molecules that 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.

“In our earlier research, we found out that the SALL4 protein works with another protein, NuRD, to form a partnership that is crucial for the development of cancers such as HCC. Instead of looking for ‘pockets’ on SALL4, our research team designed a bio-molecule to block the interaction between SALL4 and NuRD. In our lab experiments, blocking this interaction has led to tumor cell death and reduced movement of tumor cells.

This exciting discovery has important implications for treatment of HCC. Our work could also be beneficial to a broad range of solid cancers and leukemic malignancies with elevated SALL4,”

says Daniel Tenen, director of Cancer Institute of Singapore.

FFW Peptide Disruption

Further, the researchers discovered that FFW used in combination with Sorafenib can 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.

“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,”

says Liu Bee Hui, a research fellow at the Cancer Institute of Singapore.

The targeting of the SALL4-NuRD interaction as a cancer-cell-specific target represents an exciting avenue for development of therapeutic options.

“An ideal cancer target should be cancer-specific and non-toxic to normal tissues. To this end, we are collaborating to find a missing link that can cure cancer and restore normal cell function,”

explains Li Chai, an associate professor at Brigham and Women’s Hospital at Harvard Medical School.

Collaborative Effort

The research team used an integrated approach, combined with structural analysis techniques, to act on protein interactions like SALL4-NuRD. The collaborative effort 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.

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

Tenen says.

To help facilitate further research, the coordinates and structure factors of the RBBp4–SALL4 crystal complex have been recorded in the the Protein Data Bank archive RCSB database (PBD ID code 5XWR), and the RNA-seq and ChIP-seq data are available in the Gene Expression Omnibus (GEO) database,  (accession no. GSE112729).

Bee Hui Liu, Chacko Jobichen, C. S. Brian Chia, Tim Hon Man Chan, Jing Ping Tang, Theodora X. Y. Chung, Jia Li, Anders Poulsen, Alvin W. Hung, Xiaoying Koh-Stenta, Yaw Sing Tan, Chandra S. Verma, Hong Kee Tan, Chan-Shuo Wu, Feng Li, Jeffrey Hill, Joma Joy, Henry Yang, Li Chai, J. Sivaraman, Daniel G. Tenen
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
Proceedings of the National Academy of Sciences Jul 2018, 115 (30) E7119-E7128; DOI: 10.1073/pnas.1801253115