Drug fights liver cancer with fewer side effects

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Researchers have developed a new drug called FFW that could potentially stop the development of hepatocellular carcinoma (HCC) or primary liver cancer. The discovery opens the door for more effective treatments with fewer side effects.

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 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.

Researchers have widely studied 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.”

Anti-tumor properties

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,” says Daniel Tenen, director of the Cancer Science Institute of Singapore at the National University of Singapore.

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

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 Science Institute of Singapore.

New approach

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.

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.

The results of this study appear in the Proceedings of the National Academy of Science.

Source: National University of Singapore