The compound, Factor Qunolinone Inhibitor 1 (FQI1), works by inhibiting an oncogene originally discovered by a team of researchers led by Devanand Sarkar, M.B.B.S., Ph.D., Harrison Scholar at Virginia Commonwealth University (VCU) Massey Cancer Center, Blick Scholar and assistant professor in the Department of Human and Molecular Genetics and member of the VCU Institute of Molecular Medicine at the VCU School of Medicine.
Recently published in the journal Proceedings of the National Academy of Sciences, the study demonstrates that HCC cells have what is known as an "oncogene addiction" to the transcription factor Late SV40 Factor (LSF). Oncogene addiction is a term used when a cancer cell is found to be dependent on a single gene to survive. Using the compound Factor Quinolinone Inhibitor 1 (FQI1), the scientists prevented LSF from binding to HCC DNA during the transcription process, which is the first step in a series of actions that lead to cell division and duplication. This action caused rapid HCC cell death in laboratory experiments and a dramatic reduction in tumor growth in mouse models with no observable toxicity to normal liver cells.
"We may be on the verge of developing a new, effective drug for liver cancer," said Sarkar. "In the last 2 to 3 years, we demonstrated the role of LSF in liver cancer and have been screening over 110,000 compounds to identify the ones that inhibit LSF function. We identified FQI1 as one of a class of effective compounds, but we never anticipated it would work this well."
Sarkar discovered LSF's role in liver cancer in 2010 when he demonstrated significantly higher LSF levels in HCC patients in comparison to healthy individuals, and showed that inhibition of LSF reduced the progression of HCC in laboratory experiments. This finding led to the collaboration between VCU and Boston University that resulted in the discovery of FQI1.
Now that FQI1 has been identified, pharmacokinetic studies are being conducted to determine how the drug behaves in the human body. Once the scientists have determined how the drug is absorbed, distributed, metabolized and eliminated from the body, they will work with clinicians to translate their findings into phase I clinical trials in patients with liver cancer.
"We have proven this compound is effective and nontoxic in living animals," said Sarkar. "While we won't know how FQI1 reacts in humans until the first clinical trial, we are very excited by our findings and hope they lead to a new drug for a disease that is currently very difficult to treat."
The lead investigators on this study were Trevor J. Grant and Joshua Bishop, Ph.D., from Boston University. In addition to Grant and Bishop, Sarkar collaborated with Ayesha Siddiq, Ph.D., Rachel Gredler and Xue-Ning Shen, M.D., from VCU School of Medicine; Jennifer Sherman and Kevin Fitzgerald, Ph.D., from Alnylam Pharmaceuticals, Inc.; Sriharsa Pradhan, Ph.D., from New England Biolabs, Inc.; Laura A. Briggs, Ph.D., and William H. Andrews, Ph.D., from Sierra Sciences, LLC; and Lisa Christadore, Girish Barot, Ph.D., Hang Gyeong Chin, Sarah Woodson, John Kavouris, Tracy Meehan, Scott E. Schaus, Ph.D., and Ulla Hansen, Ph.D., from Boston University.
The full manuscript is available online at: http://www.pnas.org/content/early/2012/03/02/1121601109.full.pdf+html
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About VCU Massey Cancer Center: VCU Massey Cancer Center is one of only 66 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.
About VCU and the VCU Medical Center: Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 31,000 students in 211 certificate and degree programs in the arts, sciences and humanities. Sixty-nine of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.
John Wallace | EurekAlert!
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