This issue of The ASCO Post summarizes the results of an important study recently published in The New England Journal of Medicine by Yong and colleagues. As outlined, investigators from the National University of Singapore Yong Loo Lin School of Medicine have identified re-expression of SALL4 as a biomarker of aggressive hepatocellular cancer in Asian patients with the disease.

Reactivated Pathways

These investigators also provide supporting mechanistic data to suggest that SALL4 targeting can be accomplished through inhibition of SALL4’s interaction with its epigenetic co-repressor NuRD (comprising histone deacetylase 1 and histone deacetylase 2 [HDAC1 and HDAC2] complex. Inhibition of the SALL4/NuRD interaction increased expression of PTEN, resulting in dephosphorylation of AKT and thereby leading to inhibition of hepatocellular carcinoma cell growth and tumor formation.

The study is important in that it again demonstrates that pathways that are active during embryonic organogenesis and repressed in adulthood are often reactivated during carcinogenesis and that detecting such altered expression allows us to identify patients whose prognosis is negatively affected. Furthermore, as beautifully demonstrated in this study, developing a detailed understanding of the mechanism whereby SALL4 re-expression alters hepatocellular carcinoma biology can lead to a novel promising approach to treat a disease like hepatocellular carcinoma, which is enormously heterogeneous and therefore extraordinarily difficult to treat.

Cell-penetrating Peptide

A particularly interesting aspect of the study is the development of a potentially therapeutic protein generated by fusing the SALL4/NuRD inhibitory peptide with the transactivator of transcription (TAT) protein transduction domain. This domain is known to be a cell-penetrating peptide that when fused with other peptides can facilitate transit across the cell membrane; it also carries a nuclear localization signal that allows translocation of the fused protein into the cell nucleus.

Using this system, the investigators demonstrated convincing suppression of tumor growth using a xenograft model of hepatocellular carcinoma. However, it would have been exciting to also demonstrate that the fusion proteins could be detected in the cancer cells growing in the mice after intraperitoneal administration, and that the downstream consequences of inhibiting the SALL4/NuRD interaction (upregulation of PTEN and dephosphorylation of AKT) selectively occurred in the nonmutant SALL4/NuRD inhibitory fusion peptide–treated tumors in vivo.

Nevertheless, these results are exciting. In addition to further study in Asian patients with hepatocellular carcinoma, the frequency that SALL4 is overexpressed should also be examined in Western patient populations. Asian patients with hepatocellular carcinoma typically have underlying liver disease due to chronic infection with hepatitis B virus, whereas Western patients are more likely to have hepatitis C virus infection or alcohol as hepatocarcinogens. Whether these etiologic differences affect SALL4 expression should be determined.

Future Challenge

The future challenge may be for preclinical scientists to further refine the TAT protein delivery system for clinical use or to develop a small molecule that can mimic the effects of the peptide used to competitively inhibit the interaction between SALL4 and the NuRD complex. Alternatively, patients with high expression of SALL4 may be particularly good candidates for small molecules already known to inhibit PI3K/AKT signaling.

Whatever approach is taken, it is encouraging to see that patients with hepatocellular carcinoma may be able to benefit from ongoing efforts to provide precise therapies for these otherwise dauntingly complex malignancies. ■

Disclosure: Dr. Abbruzzese reported no potential conflicts of interest.