Originally published as JCO Early Release 10.1200/JCO.2005.14.498 on May 2 2005

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The Theoretical Basis of Transcriptional Therapy of Cancer: Can It Be Put Into Practice?

Ari M. Melnick, Kerin Adelson, Jonathan D. Licht

From the Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx; Divisions of Hematology and Oncology, Columbia University College of Physicians and Surgeons; and Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY

Address reprint requests to Jonathan D. Licht, MD, Mount Sinai School of Medicine, Box 1079, One Gustave L. Levy Place, New York, NY 10029; e-mail: jonathan.licht{at}mssm.edu.

Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair–related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. Recent discoveries in transcriptional biochemistry and gene regulation indicate that therapeutic agents can be engineered to specifically target these mechanisms. We provide a framework for the clinical or translational scientist to consider how such drugs might be developed and what their impact might be on restoring cells to normal genetic programming.

Supported by RO1 CA59936 and a Burroughs Welcome Foundation Clinical Scientist Award in Translational Research (J.D.L.); the Empire Clinical Research Investigator Program (K.A.); and RO1 CA99982 and a Sidney Kimmel Cancer Foundation Scholar Award (A.M.M.).

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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