Scientists ID Gene Linked to Aggressive Liver Cancer

Finding, though preliminary, might lead to better treatments

Wednesday, June 12, 2013

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WEDNESDAY, June 12 (HealthDay News) -- Researchers have found a gene they say can help identify patients facing aggressive liver cancer, and may prove key to their future treatment.
This is good news in a field "that has not had big advances before this and has not been the beneficiary of genomic medicine," said Dr. Richard Goldberg, a professor of medicine at the Ohio State University Comprehensive Cancer Center.
The new laboratory study focused on hepatocellular carcinoma, a type of cancer that originates in the liver, particularly in people who have sustained liver damage from diseases such as hepatitis or cirrhosis, said Goldberg, who was not involved in the research. The findings open the possibility of targeted drugs that would outperform the standard drug treatment in use now, he said.
Some patients with hepatocellular carcinoma -- the most common form of liver cancer -- appear to have overactivity of a gene that is most often linked to embryonic stem cells and early human development, according to the study, published June 13 in the New England Journal of Medicine.
Those patients had a worse prognosis than other patients with hepatocellular carcinoma, wrote the lead authors from the National University of Singapore.
Further, blocking the gene -- called SALL4 -- appeared to help stop the cancer's spread, the researchers said.
Dr. Snorri Thorgeirsson, chief of the Laboratory of Experimental Carcinogenesis with the Center for Cancer Research at the U.S. National Cancer Institute, considers the new findings significant. "They found that if they inhibited SALL4, they were able to slow the growth of the cancer quite drastically," said Thorgeirsson. "They did this in lab cultures and in animal testing. It's pretty impressive they were able to show this."
Liver cancer is a leading cause of cancer-related deaths globally. More than 700,000 people are diagnosed with liver cancer each year throughout the world, and it accounts for more than 600,000 deaths annually, according to the American Cancer Society. Overall, the five-year survival rate from liver cancer is about 15 percent.
SALL4 has previously been linked to leukemia and other types of cancer, according to the study authors.
The researchers obtained specimens from 179 people with liver cancer and performed microscopic analysis to determine the number of cancer cells that appeared to contain the SALL4 gene.
Next, lab tests were performed to determine the effect of the SALL4 gene on liver cancer cells, using a peptide drug to block the gene's activity in mice and human samples. The cancer slowed as a result.
At this point, SALL4 will be most useful to help figure out liver cancer patients most in need of treatment, said Thorgierrson, co-author of an editorial that accompanied the new study.
"Now you can use SALL4 as a biomarker," he said. "If you find patients who overexpress this gene, you can focus treatment on them."
Most people are diagnosed with hepatocellular carcinoma when it's in an advanced stage. At that point the standard treatment option is a drug called sorafenib (Nexavar), and most patients don't respond to it, said Goldberg. "It's better than what we had before, but it doesn't affect the outcome for the majority of patients," he said. The current research suggests it may be possible to develop a new type of drug that would perform better, he said.
The gene also can be used to figure out which liver cancer patients might most benefit from experimental drugs that target the cancer's developmental signaling pathways, said Michael Melner, program director of molecular genetics and biochemistry of cancer for the American Cancer Society.
"I think more research needs to be done on their particular target and its effectiveness," Melner said. "It may be in the future that this SALL4 ends up being a good target, but it's a little early based on the evidence so far to make that jump. But this could be a very good biomarker for separating groups of patients that then could be treated with different classes of these newly developed classes of therapeutic drugs."
It is unlikely that the peptide used to block SALL4 in this study would be a viable drug for liver cancer patients, Melner said.
"A number of drug companies have tried peptide-based drugs," he said. "Although the drugs are effective, they need to be present in relatively high concentrations. It's been difficult to achieve those levels in humans."
However, clinical trials are under way involving targeted drugs that inhibit the expression of genes with stem-cell features, Thorgierrson noted.
"These will also affect SALL4, so there may already be available drugs that can be a potentially useful treatment," he said. "This needs to be expanded into proper medical trials, but the data set is very impressive."

SOURCES: Snorri Thorgeirsson, M.D., Ph.D., head, Center of Excellence in Integrative Cancer Biology and Genomics, and chief, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, U.S. National Cancer Institute, Bethesda, Md.; Michael Melner, program director, molecular genetics and biochemistry of cancer, American Cancer Society, Atlanta; Richard Goldberg, M.D., professor, medicine, Ohio State University Comprehensive Cancer Center, and associate editor, gastrointestinal cancers, American Society of Clinical Oncology, Cancer.Net; June 13, 2013, New England Journal of Medicine

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