A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.

Abstract

e13505 Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.