From left: Robert A. Casero, Ph.D., Cynthia Zahnow, Ph.D., Stephen Baylin, M.D.
Johns Hopkins University

Novel Therapies Targeting Epigenetic Silencing of Tumor Suppressors

The overarching goal of this continuing collaborative effort is to combine the expertise of three laboratories whose unifying purpose is to develop novel strategies and agents that target aberrant epigenetic gene silencing of genes in cancer. Epigenetic silencing results from changes in DNA where DNA bases are modified without changing the actual DNA sequence. This is called DNA methylation. Another epigenetic change that regulates gene expression is the modification of histone proteins, proteins that bind to DNA and control its transcription.

Aberrant epigenetic silencing of tumor suppressor genes, genes that block cancer growth, is critically important in the initiation and progression of essentially all tumors. Unlike mutations epigenetic silencing has the potential to be reversed and is thus an attractive target for treating cancer. This collaborative program has the advantage of combining three investigators whose interest directly compliment each other.

Dr. Casero (Project 1) is a molecular pharmacologist whose laboratory aided in the discovery of the first documented lysine-specific demethylase, LSD1, a histone-modifying enzyme that is capable of broadly and aberrantly Silencing gene expression. Dr. Casero's project will investigate the utility of inhibiting LSD1 activity, using recently discover LSD1 inhibitors, alone and in combination with other agents, as a strategy for antitumor therapy.

Dr. Zahnow's (Project 2) expertise is in breast cancer and in understanding how aberrant epigenetic silencing interacts with, and disrupts normal cellular signaling and leads to tumorigenesis. She has extensive experience with mouse models of cancer and has developed several unique tumor models in mice using breast cancer cell lines and primary samples from cancer patients to test the anti-tumor effects of epigenetiC therapies. Dr. Zahnow's project will focus on the combination of epigenetically targeted agents in combination with standard chemotherapeutic agents to optimize such a strategy for clinical use.

Finally, Dr. Baylin (Project 3), is an expert in cancer epigenetics and helped develop and refine the concepts of how promoter DNA methylation, in concert with chromatin modification, act in concert to initiate and maintain silencing of genes. Further, his laboratory has been instrumental in bringing strategies of targeting aberrant epigenetic gene regulation to the clinic, with a particular recent focus on' solid tumors. Dr. Baylin's project will expand upon his laboratories recent findings about the important possibilities that epigenetic therapies may reprogram, and inhibit, key subpopulations of cancer "stem-like" cells, the cells from which cancers are thought to arise. The studies in this project will help inform the studies in Projects 1 and 2, with the goal of using the information gained to rapidly translate laboratory findings into clinical applications.

In summary, this collaborative effort will seek to exploit the dysregulation of epigenetic gene silencing in cancer as a strategy for treatment. Specifically, we will focus on solid tumors with an emphasis on breast cancer, to design, refine, and introduce into clinical trials combination treatments designed to reference aberrant gene silencing, while minimizing toxicity and optimizing response.