Until now, there has been no effective, systemic treatment for liver cancer (hepatocellular carcinoma), the fifth most common cancer worldwide. Writing in the Proceedings of the National Academy of Science (PNAS), Professor Scott Schaus (Chemistry) and Professor Ulla Hansen (Biology and Molecular Biology, Cell Biology & Biochemistry) have reported their discovery of a new protein target for chemotherapy in the treatment of liver cancer — the transcription factor LSF. LSF occurs at high levels in the tumor tissue of patients with liver cancer and is known to promote the development of cancer (oncogenesis) in studies using laboratory rodents.
The co-investigators have identified small molecules that effectively inhibit LSF cellular activity, which in turn slows the growth of the cancer. In particular, they found that one such molecule, Factor Quinolinone Inhibitor 1 (FQI1), derived from a lead compound, inhibits 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. 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 characteristic is very encouraging for use
of such compounds clinically.
Following 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.
Citation: T.J. Grant, J. A. Bishop, L.M. Christadore, G. Barot, H.G. Chin, S. Woodson, J. Kavouris, A. Siddiq, R. Gedler, X-N. Shen, J. Sherman, T. Meehan, K. Fitzgerald, S. Pradhan, L.A. Briggs, W.H. Andrews, D. Sarkar, S.E. Schaus, and U. Hansen, “Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma,” Proc. Natl. Acad. Sci. U.S.A., March 20, 2012, Vol. 109, No. 12, 4503-4508.
The Ignition Award Program provides funds to evolve BU research to the stage where it can be licensed, form the basis of a new company, or be used to create a new, non-profit social enterprise. In June 2010, two Chemistry faculty, John Porco and John Snyder, received these highly competitive awards for their respective commercially promising projects.
Professor Porco’s research is the “Development of Novel Protein Synthesis Inhibitors as Chemotherapeutic Agents.” The work will involve synthesis of novel silvestrol (rocaglate) derivatives and their evaluation as protein translation inhibitors in the Pelletier laboratory at McGill University. Promising derivatives will be tested in the National Cancer Institute’s 60 cancer cell line panel and then advanced to animal models for B-cell leukemias and other cancers that are highly susceptible to translational control.
Professor Snyder’s research focuses on the “Development of New Anti-Tuberculosis Agents.” Three synthetic compounds from the Center for Chemical Methodology and Library Development (CMLD-BU) were determined to be “hits” against Mycobacterium tuberculosis, the tuberculosis-inducing microorganism. The preliminary biological activity data against M. tuberculosis, coupled with the unique structures of the lead compounds have justified advancing these compounds toward commercialization through the biological assays needed to establish the scope of activity and bioavailability.