Despite the prevalence of this disease, until now there has been no effective, systemic treatment. Thanks to a team of researchers in Boston University’s Departments of Biology and Chemistry, and the Program in Molecular Biology, Cell Biology, and 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.
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.
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) (www.pnas.org/lookup/suppl/doi:10.1073/pnas.1121601109). The co-principal investigators are Ulla Hansen, Professor of Biology, and Scott Schaus, Associate Professor of Chemistry, Boston University.
Contributing authors are Trevor J. Grant, Girish Barot, Hang Gyeong Chin, Sarah Woodson, Jennifer Sherman, and Tracy Meehan, Department of Biology, Boston University; Joshua A. Bishop, Lisa M. Christadore, and John Kavouris, Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University; Sriharsa Pradhan, New England BioLabs, Inc., Ipswich, MA; Ayesha Siddiq, Rachel Gredler, Xue-Ning Shen, and Devanand Sarkar, Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA; Laura A. Briggs and William H. Andrews, Sierra Sciences, LLC, Reno, NV; and Kevin Fitzgerald, Alnylam Pharmaceuticals, Inc., Cambridge, MA.
About Boston University—Founded in 1839, Boston University is an internationally recognized private research university with more than 30,000 students participating in undergraduate, graduate, and professional programs. As Boston University’s largest academic division, the College and Graduate School of Arts & Sciences is the heart of the BU experience with a global reach that enhances the University’s reputation for teaching and research.
Contact information for the authors:Ulla M. Hansen, Professor
Scott E. Schaus | Newswise Science News
Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University
Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
27.02.2017 | Materials Sciences
27.02.2017 | Interdisciplinary Research
27.02.2017 | Life Sciences