Cynthia Zahnow, Ph.D., is on the cutting edge of epigenetic-targeted therapy, an emerging field of cancer discovery and clinical promise made possible by pioneering discoveries at the Johns Hopkins Kimmel Cancer Center. Epi- (in addition to) genetic refers to abnormal biochemical alterations to the environment of DNA that can cause cancers to form, grow, and spread. These non-mutational alterations have been referred to as “the ghosts in our genes” because they alter gene function without the telltale mark of mutation. Instead, key tumor suppressor genes are silenced by chemical changes.
The Kimmel Cancer Center is considered the international leader in epigenetics research with more citations than any other academic medical institution. Dr. Zahnow, the Evelyn Grolman Glick Scholar, is working with leading epigenetics researcher Stephen Baylin to apply this science to breast and lung cancer treatment.
Her most recent research focuses on two drugs (azacitidine and decitabine) that work to correct these cancer-causing epigenetic alterations. The research has provided some of the first laboratory evidence that low, non-toxic doses of the targeted drugs cause antitumor responses in the most common types of cancer, including breast, lung, and colon cancers.
Unlike standard forms of chemotherapy, which are typically given at high doses and indiscriminately poison and kill rapidly dividing cells, including cancer cells, epigenetic-targeted therapy reprograms cells. This promising new area of discovery represents a revolutionary paradigm shift in cancer treatment. A dead cell cannot be reprogrammed, so this type of drug research is not about killing cancer cells quickly, but rather about keeping them alive and rewiring them so they return to a normal state. Therefore, Dr. Zahnow, assistant professor of oncology, and team use the lowest possible doses of drugs, doses that do not kill cancer cells outright but rather repair the broken mechanisms and revert them back to a more normal state—one with a normal life cycle. As a result, these therapies kill cancer cells more slowly over time as they make their repairs and genes are returned to normal function. The low doses also mean that these drugs work without causing the sometimes serious and quality-of-life altering side effects so closely associated with cancer treatment. For Dr. Zahnow, herself a breast cancer survivor, the value of being able to effectively treat cancer without causing potentially serious and cumulative adverse effects to patients cannot be under estimated.
In her research, Dr. Zahnow found that the low-dose epigenetic treatment works through many cancer cell gene pathways, including those that control cell cycle, DNA repair, cell maturation or differentiation, immune cell interaction, and cell death. Her studies continue, but she finds that epigenetic-targeted therapy works, in part, by reversing the aberrant chemical alterations to cell DNA. This leads to reactivation of silenced tumor suppressor genes needed to halt tumor growth and blocks other genes that fuel the growth of tumors. Her laboratory findings also indicate that this therapy takes aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade cancer treatment and lead to cancer recurrence and spread.
This type of targeted treatment is part of the Kimmel Cancer Center’s growing arsenal of personalized approaches to cancer. Dr. Zahnow believes the best results will come in patients whose cancers match a specific epigenetic and genetic profile. She and her collaborators continue to work to define the specific cellular alterations that will best respond to the treatment. In earlier lung cancer trials, a small subset of patients with tumors that had been unresponsive to standard treatments experienced remarkable responses. Clinical trials in breast cancer have now begun.
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Zahnow, C.A.; Baylin, S.B. Epigenetic networks and miRNAs in stem cells and cancer. Mol Cell. 2010 Sep 10;39(5):661-663
Zahnow, C.A. CCAAT/enhancer-binding protein beta: its role in breast cancer and associations with receptor tyrosine kinases. Expert Rev Mol Med. 2009;11:e12.
Chen, H.; Lee, J.S.; Liang, X.; Zhang, H.; Zhu, T.; Zhang, Z.; Taylor, M.E.; Zahnow, C.; Feigenbaum, L.; Rein, A.; Sukumar, S. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 2008 May 15;68(10):3637-3644.
Biankin, S.A.; Collector, M.I.; Biankin, A.V.; Brown, L.J.; Kleeberger, W.; Devereux, W.L.; Zahnow, C.A.; Baylin, S.B.; Watkins, D.N.; Sharkis, S.J.; Leach, S.D. A histological survey of green fluorescent protein expression in 'green' mice: implications for stem cell research. Pathology. 2007 Apr;39(2):247-251.
Zahnow, C.A. ErbB receptors and their ligands in the breast. Expert Rev Mol Med. 2006;8(23):1-21.