Funded Investigators
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| Paul B. Fisher, M.Ph., Ph.D. | Devanand Sarkar, M.B.B.S., Ph.D. |
| Virginia Commonwealth University | Virginia Commonwealth University |
LSF as Oncogene and Target for Therapies in Hepatocellular Carcinoma
Liver cancer (hepatocellular carcinoma; HCC) is a highly fatal disease with no effective treatment available for the advanced, metastatic disease. As such understanding the molecular mechanism of liver cancer development and progression is mandatory to develop novel and effective therapies. They have recently identified that the transcription factor LSF is a novel oncogene for HCC. LSF expression is significantly higher in more than 90 percent of human HCC cases compared to normal liver. Forced overexpression of LSF in poorly aggressive human HCC cells results in highly aggressive multi-organ metastatic tumor in nude mice. Conversely, inhibition of LSF in highly aggressive human HCC cells significantly abrogates their tumorigenic and metastatic properties in nude mice.
These findings strongly suggest that LSF plays an important role in regulating hepatocarcinogenesis and therapeutic approaches might be developed targeting LSF. They have developed a small molecule inhibitor of LSF termed FQI1. FQI1 inhibits LSF and profoundly inhibits the viability of human HCC cells in vitro. Additionally, FQI1 also markedly inhibited growth of human HCC cells implanted subcutaneously in athymic nude mice. More importantly, treating the animals with FQI1 did not demonstrate any toxic effects indicating that FQI1 is safe and non-toxic to normal cells.
These provocative preliminary studies strongly suggest that FQI1 might be a novel and effective therapeutic option for HCC and mandates more stringent evaluation of its efficacies in animal models. In the present proposal, they will analyze the efficacy of FQI1 in orthotopic (in the liver) human HCC model in nude mice as well as in transgenic mouse models that spontaneously develop HCC.
Additionally, in collaboration with Dr. Josep Llovet, they will analyze human HCC sections for LSF expression to establish LSF as a diagnostic/prognostic marker for HCC. Successful completion of the proposed studies will accrue the baseline information to start a phase I/II clinical trial with FQI1 as well as identify a novel marker for HCC. Thus the present proposal has immense translational implication.
