Retinoic acid is a form of vitamin A that is used to treat and help prevent the recurrence of a variety of cancers, but for some patients the drug is not effective. The reason for this resistance was unclear until this week when researchers from Virginia Commonwealth University (VCU) Massey Cancer Center demonstrated that a protein known as AEG-1 blocks the effects of retinoic acid in leukemia and liver cancer. Because AEG-1 is overexpressed in nearly every cancer, these findings could impact the care of countless cancer patients.
Details of the study were published this week in the online edition of the journal Cancer Research, a journal of the American Association for Cancer Research. The team of scientists led by Devanand Sarkar, M.B.B.S., Ph.D., demonstrated that the protein AEG-1 binds to retinoid X receptors (RXR), which help regulate cell growth and development. RXR is typically activated by retinoic acid, but the overexpressed AEG-1 proteins found in cancer cells block these signals and help promote tumor growth. Using complex animal models, the researchers showed that blocking the production of AEG-1 allowed retinoic acid to profoundly kill liver cancer cells.
"Our findings are the first to show that AEG-1 interacts with the retinoid X receptor," says Sarkar, Harrison Scholar at VCU Massey Cancer Center, Blick Scholar and associate professor in the Department of Human and Molecular Genetics and member of the VCU Institute of Molecular Medicine (VIMM) at VCU School of Medicine. "This research has immediate clinical relevance such that physicians could begin screening cancer patients for AEG-1 expression levels in order to determine whether retinoic acid should be prescribed."
Sarkar and his colleagues have been studying AEG-1 for years. They were the first to create a mouse model demonstrating the role of AEG-1 in liver cancer, and they have been actively working to develop targeted therapies that block AEG-1 production. The present study expanded their knowledge of the molecular interactions of AEG-1.
"We are continuing to test combination therapies involving AEG-1 inhibition and retinoic acid in animal models, and the initial results are promising," says Sarkar. "If we continue to see these results in more complex experiments, we hope to eventually propose a phase 1 clinical trial in patients with liver cancer."
Sarkar collaborated on this study with Paul B. Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at Massey, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM; Jolene Windle, Ph.D., professor in the Department of Human and Molecular Genetics at the VCU School of Medicine and Irene Shaw Grigg Distinguished Professor in Genetics Research, co-leader of the Cancer Molecular Genetics research program and resource director of the Transgenic/Knock-out Mouse Facility at Massey; Luni Emdad, M.B.B.S., Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor in the Department of Human and Molecular Genetics at the VCU School of Medicine; Jyoti Srivastava, Ph.D., Chadia L. Robertson, Devaraja Rajasekaran, Ph.D., Rachel Gredler and Ayesha Siddiq, Ph.D., all from the Department of Human and Molecular Genetics at the VCU School of Medicine; Shobha Ghosh, Ph.D., associate chair for research in the Department of Internal Medicine at the VCU School of Medicine; Phillip B. Hylemon, Ph.D., member of the Cancer Cell Signaling research program at Massey and professor of microbiology and immunology at the VCU School of Medicine; Gregorio Gil, Ph.D., professor of biochemistry and molecular biology at the VCU School of Medicine; and Khalid Shah, Ph.D., and Deepak Bhere, Ph.D., from Harvard Medical School.
This study was supported by National Cancer Institute grant R01 CA 138540; National Institutes of Health grant R01 CA134721; the James S. McDonnel Foundation; and, in part, by VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.
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