Oncofetal Gene May Be Marker for Aggressive Liver Cancer

Laurie Barclay, MD

June 13, 2013

The discovery that an oncofetal gene, SALL4, appears to be a marker for aggressive liver cancer has ignited hope that it can be used to screen patients and that it will offer a new target for drug development.

"Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide," Kol Jia Yong, BSc, from the Cancer Science Institute of Singapore and the National University of Singapore, and colleagues write in their report published in the June 13 issue of the New England Journal of Medicine.

"In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment," they note.

The investigators screened specimens from patients with primary hepatocellular carcinoma to detect SALL4 expression. They then conducted loss-of-function studies to determine the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. In vitro functional and in vivo xenograft assays allowed them to evaluate the therapeutic effects of a peptide targeting SALL4.

The stem-cell factor SALL4 was expressed in the human fetal liver but not in the healthy adult liver. However, in a subgroup of patients with hepatocellular carcinoma and an unfavorable prognosis, the SALL4 oncofetal protein was re-expressed.

Gene-expression analysis revealed that in SALL4-positive hepatocellular carcinomas, progenitor-like gene signatures are enriched and proliferative and metastatic genes are overexpressed. SALL4 is essential for cancer cell survival and tumorigenicity, according to loss-of-function studies.

In xenograft models in vivo, blocking SALL4–corepressor interactions released suppression of the phosphatase and tensin homolog protein and inhibited tumor formation. These findings add biologic credibility to SALL4 as a prognostic marker and suggest that targeting this pathway could be of therapeutic value.

Study Limitations and Implications

"The discovery of a role for SALL4 in hepatocellular carcinoma, its association with prognosis, and the antitumor effects of a newly identified peptide blocker targeting it have potential therapeutic significance," the investigators conclude. "Testing for the presence of SALL4 at diagnosis may be helpful not only for determining the prognosis but also for identifying patients who are likely to have a response to treatment. Given the expression of SALL4 in hepatocellular carcinoma cells but not in normal adult hepatocytes, treatment with SALL4 peptide may have less tissue toxicity, which is especially beneficial in patients with underlying cirrhosis whose baseline liver function is already compromised."

Limitations of this study include the retrospective design. The investigators recommend prospective clinical trials to verify the prognostic value of SALL4 and to determine whether it has synergistic potential with sorafenib or other molecular therapies that act on parallel nonoverlapping pathways.

In an accompanying editorial, Jens U. Marquardt, MD, from the National Cancer Institute in Bethesda, Maryland, and colleagues note that hepatocellular carcinoma is the most common and deadly cause of primary liver cancer. Most patients with hepatocellular carcinoma still present at advanced stages, when there are limited curative options.

"Currently, the standard-of-care treatment for advanced liver cancer is limited to the multiple receptor tyrosine kinase inhibitor sorafenib," the editorialists write. "Furthermore, development of new therapies is often hampered by the molecular complexity of hepatocellular carcinoma, as well as associated inflammatory and fibrotic liver disease. Results of ongoing clinical trials are discouraging overall, and they highlight the urgent and unmet need for innovative treatment approaches in patients with advanced stages of hepatocellular carcinoma."

Therapeutic Potential of Targeting SALL4

The editorialists call the study findings "convincing," but insufficient to determine whether the targeting of SALL4 alone has enough antitumor activity to prevent recurrent disease, or whether inhibition of the associated transcriptomic programs is also required.

"Another open question is whether responses to SALL4 inhibition in stemness-associated tumors vary according to the patient's ethnic origin and the cause of the hepatocellular carcinoma (e.g., hepatitis B virus, hepatitis C virus, and alcohol); this variability has been repeatedly observed in other targeted therapies," Dr. Marquardt and colleagues write. "Also, the present data do not resolve whether tumors that overexpress SALL4 are derived from reprogrammed hepatocytes or rare stem cells; the latter might have a major effect on the regenerative capacity of the liver and should be considered in a therapeutic context."

Interim results from an ongoing phase 2 trial of the HDAC inhibitor resminostat appear to be promising and may now warrant further subgroup analyses according to SALL4 status.

Similarly, these findings support those from a phase 2 trial of the c-MET inhibitor tivantinib, which demonstrate that biopsies are mandatory for molecular subclassification in patients with advanced hepatocellular carcinomas.

The study findings "elegantly show the benefit of innovative treatment strategies in hepatocellular carcinoma, including the targeting of genes with stem-cell features such as SALL4," the editorialists conclude. "Clinical translation of these important findings is urgently needed to achieve individualized therapies and ultimately improve the poor outcome in patients with hepatocellular carcinoma."

A press release from the National University of Singapore notes that 2 patents have already been filed on this research. It also notes that, because SALL4 is associated with other types of cancers, such as leukemia and solid tumors (including ovarian, endometrial, gastric, breast and lung cancers), the findings could contribute to an improvement in the treatment of such diseases.

The Singapore National Medical Research Council and grants from the Singapore Ministry of Education, National Research Foundation, and the National Institutes of Health funded this study.

N Engl J Med. 2013;368:2266-2276, 2316-2318. Abstract, Editorial

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