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Hepatocellular carcinoma (HCC), or primary cancer of the liver, is the fifth most common cancer worldwide. Despite the prevalence of this disease, until now there has been no effective, systemic treatment. Thanks to a team of researchers in the CAS departments of biology and chemistry, and the program in molecular biology, cell biology & biochemistry, that may be about to change.
The BU research team and collaborators recently discovered a promising new protein target for chemotherapy in the treatment of liver cancer—the transcription factor LSF. (Transcription factors are regulatory proteins that bind genomic DNA near the start of genes, either promoting or inhibiting the transcription or copying of the gene.) LSF is found in high levels in the tumor tissue of patients with liver cancer and has been demonstrated to promote the development of cancer (oncogenesis) in studies using laboratory rodents.
The team’s findings have been published in the article “Antiproliferative small molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma” in the Proceedings of the National Academy of Science (PNAS) (citation details). The co-principal investigators are Professor of Biology Ulla Hansen and Associate Professor of Chemistry Scott Schaus.
Central to their findings, the BU scientists identified small molecules that effectively inhibit LSF cellular activity, which in turn slows the growth of the cancer. In particular, one such molecule, called Factor Quinolinone Inhibitor 1 (FQI1), derived from a lead compound, was found to inhibit the ability of LSF to bind DNA both in extracts (in vitro, as determined by electrophoretic mobility shift assays), and in cells. Consistent with inhibiting LSF activity, FQI1 also eliminates the ability of LSF to turn up transcription. FQI1 also demonstrates antiproliferative activity, or the ability to prevent or retard the growth of cells. While FQI1 quickly causes cell death in LSF-overexpressing cells, including liver cancer cells, healthy cells are unaffected by the treatment.
This phenomenon has been called oncogene addiction, where tumor cells are “addicted” to the activity of an oncogenic factor for their survival, but normal cells can do without it. This is very encouraging for use of such compounds clinically. Quantitative analysis of FQI1 (based on a concordant structure-activity relationship of a panel of 23 quinolinones) strongly suggests that its growth inhibitory activity focuses on a single biological target or family. This focus, coupled with the striking correlation between the concentrations required for antiproliferative activity and for inhibition of LSF transactivation, indicates that LSF is that specific biological target of FQI1.
Building on the in vitro trials, the researchers tested the efficacy of FQI1 in inhibiting liver cancer tumor growth by injecting HCC cell lines into rodent models. FQI1 was observed to significantly inhibit tumor growth with no observable side effects (general tissue cytotoxicity). These dramatic findings support the further development of LSF inhibitors as a promising new chemotherapy treatment for liver cancer.
Read a BU Today article on this research.