Therapeutic has applications in treating liver cancers and leukemias

By Jessica Lau

Summary

• Scientists have engineered a therapeutic molecule that blocks SALL4, a protein involved in about one-third of cancers, in mice.
• This therapeutic approach could be applied to treating liver cancers and leukemias.

In about a third of cancers, a protein called SALL4 attaches to DNA in the cells and unleashes a cascade of activity that helps the cancer grow. The protein has been considered “undruggable,” since there is nowhere on its surface for an inhibiting drug to bind.

By taking a new approach to analyzing the SALL4 structure, scientists at the Cancer Science Institute of Singapore (CSI Singapore), the National University of Singapore (NUS), and the Harvard Stem Cell Institute (HSCI) have developed a therapeutic molecule that blocks the protein and prevents tumor growth in mice.

The findings are published in Proceedings of the National Academy of Sciences of the United States of America.

Starving cancers of SALL4

SALL4 is not active in healthy adults — only in embryos and cancers.

“When human embryos are growing, the SALL4 gene is active, but at a certain point it shuts off permanently,” said Li Chai, M.D. “So, consider this: about a third of cancers, including leukemia and liver cancer, depend on SALL4 being active to survive. We want to make a therapy that starves them of it.”

Chai is an Associate Professor of Pathology at Brigham and Women's Hospital, Harvard Medical School. She is a senior author on the study, along with J. Sivaraman, Ph.D., Professor in the Department of Biological Sciences at NUS, and Daniel Tenen, M.D., leader of the HSCI Blood Program, Professor of Medicine at Harvard Medical School, and Director of CSI Singapore.

In this study, the researchers capitalized on the fact that SALL4 needs to interact with other proteins in order to work. First, they analyzed the structure of SALL4 when it was bound to one of these other proteins, RBBp4. Then, they engineered a molecule with a stronger ability to bind to SALL4, effectively outcompeting RBBp4.

When the researchers tested the engineered molecule in a mouse model of hepatocellular carcinoma — a type of liver cancer — the treatment limited tumor growth.

From cancer treatment to stem cell regeneration

The researchers focused on SALL4 not just because of its role in cancer growth, but also because it has potential for promoting healthy regeneration.

“We want to know the SALL4 gene inside and out,” said Tenen, looking ahead to future work. “If we knew exactly how it influences healthy growth in the embryo, we could perhaps develop a method to program adult stem cells to regenerate when we need them to.”

Learn more

Liu B. H. and Jobichen C. et al. (2018). Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proceedings of the National Academy of Sciences of the United States of America. DOI: 10.1073/pnas.1801253115