New drug may improve liver cancer therapy

Researchers from many international institutions have teamed up to design a more effective drug for liver cancer therapy. Their compound may help improve survival rates and reduce adverse effects.

Hepatocellular carcinoma, or primary liver cancer, tends to grow and expand at a fast rate.

If it is not caught early, this means that people who have been diagnosed with it may not survive longer than 11 months.

Recent studies show that in the United States, hepatocellular carcinoma is the ninth leading cause of cancer-related deaths.

To treat it, specialists will usually prescribe therapy with a drug called "sorafenib." Unfortunately, this drug typically prolongs survival by only 3 months, and it can have numerous adverse effects.

In an effort to improve liver cancer treatment, researchers from the Cancer Institute of Singapore at the National University of Singapore in Queenstown have come together with colleagues from other global institutions to develop a new experimental drug, which they call "FFW."

FFW, the scientists believe, could hinder the growth of primary liver cancer and help reduce the unwanted effects of typical therapy.

The researchers outline the process of developing FFW in a paper now published in the journal PNAS.

"In our latest work, [we have] demonstrated an effective strategy to accurately target oncogenes previously considered undruggable," says study co-author Prof. Daniel Tenen, of the National University of Singapore.

The smart workaround drug

The researchers based their new study on some earlier findings about a protein that is known to be implicated in tumor growth: SALL4.

SALL4 is seen in developing fetuses but is normally inactive in fully developed tissue. However, in liver cancer, this protein becomes active again, contributing to tumor growth.

So far, SALL4 has been considered an "undruggable target," meaning that it does not respond to drugs that target it. That is because, unlike other proteins, SALL4 does not have a "pocket" in its structure to allow drug molecules to lodge in and take effect.

Nevertheless, the research team's earlier experiments suggested a way to work around this issue.

"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 [hepatocellular carcinoma]," explains Prof. Tenen.

"Instead of looking for 'pockets' on SALL4, our research team designed a biomolecule to block the interaction between SALL4 and NuRD," he adds.

By blocking the interaction between SALL4 and NuRD, the biomolecule FFW "has led to tumor cell death and reduced movement of tumor cells," Prof. Tenen observes.

Moreover, when used in conjunction with sorafenib, FFW may also be able to hinder the growth of liver cancer that is resistant to this drug.

Aiming 'to find a missing link'

The researchers' experimental compound is a peptide drug. Compared with small molecule drugs, peptide drugs act with more precision, which also means that it is potentially less toxic; it will not affect healthy tissue.

"An ideal cancer target should be cancer-specific and non-toxic to normal tissues," says study co-author Li Chai, an associate professor from Brigham and Women's Hospital at Harvard Medical School in Boston, MA.

"To this end," she adds, "we are collaborating [cross-institutionally] to find a missing link that can cure cancer and restore normal cell function."

If the researchers perfect the peptide drug — and perhaps develop other, similar compounds — they hope to use them to tackle a series of other cancers that are SALL4-dependent.

"Our work could also be beneficial to a broad range of solid cancers and leukemic malignancies with elevated SALL4," notes Prof. Tenen.