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Targeting Histones and Proteasomes: New Strategies for the Treatment of Lymphoma

Owen A. O'Connor

From the Laboratory of Experimental Therapeutics for the Lymphoproliferative Malignancies, Department of Medicine, Division of Hematologic Malignancies, Lymphoma and Developmental Chemotherapy Services, Memorial Sloan Kettering Cancer Center, New York, NY

Address reprint requests to Owen A. O'Connor, MD, PhD, Department of Medicine, Lymphoma and Developmental Chemotherapy Services, Box 329, 1275 York Ave., New York, N.Y. 10021; e-mail: oconnoro{at}mskcc.org.

Our ever-increasing understanding of cancer cell biology has begun to provide a variety of new, and potentially drugable targets for the treatment of many forms of cancer. Nowhere else is this more apparent than in the treatment of the lymphomas. A rapidly emerging experience in gene expression profiling has begun to suggest that we can define different subtypes of lymphoma on the basis of unique molecular signatures. These signatures can define important signaling pathways that may help account for the biology of different subsets of lymphoma, and are teaching us that the lymphomas are truly a heterogeneous set of diseases. What remains equally as interesting is the idea that empiric observations of novel targeted drugs in select subtypes of lymphoma can teach us much about the biology of different lymphomas. A priori assumptions about the anticipated activity of novel targeted agents in select subtypes of lymphoma have been turned upside down. Two pathways that have emerged recently as potentially important targets for new agents in lymphoma include the ubiquitin proteasome pathway and the biochemical reactions that control histone acetylation. New classes of drugs that affect these targets, such as bortezomib, depsipeptide, suberoylanilide hydroxamic acid, and a host of other compounds, though affecting a unique target in the cell, are associated with a remarkable panoply of different downstream biologic effects. In this article, we will review some of the prevailing theories about how these novel targeted drugs affect lymphoma biology, and how these compounds are changing the face of lymphoma therapy.

O.A.O. is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award.

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

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