Recently reported in PNAS, Bjoern Reinhard and his collaborator at the BU Medical School, Dr. Suryaram Gummuluru, have confirmed a unique HIV-1 DC attachment mechanism using lipoparticles with defined surface composition. The mechanism is dependent on a host-cell–derived ligand, GM3, and is a unique example of pathogen mimicry of host-cell recognition pathways that drive virus capture and dissemination in vivo. These insights provide the basis for the development of artificial virus nanoparticles with host-derived surface groups that inhibit the HIV-1 trans-dissemination pathway through dendritic cells. The virus parasite uses these dendritic cells to facilitate its dissemination, while avoiding recognition.
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.
Published in PNAS in July 2011, the paper represents their collaborative work with researchers in the BU Department of Mathematics and Statistics, Professor Eric Kolaczyk and Graduate Student Lisa Pham.
It reports on the effectiveness of their novel method, latent pathway identification analysis (LPIA), in providing insights into systemic biological pathways and key cellular mechanisms that dictate disease states, drug response, and altered cellular function. The work was supported by NIH, NSF, and DOD.