Epigenetics Changes in Cancer Cells

Highlights of the American Association for Cancer Research Special Conference on Chromatin, Chromosomes, and Cancer Epigenetics; November 10-14, 2004; Waikoloa, Hawaii

Kris Novak, PhD

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In This Article

Targeting DNMT Enzymes: Benefits and Risks

Rudolf Jaenisch,[6] of the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, another researcher who studies the role of stem cells in tumor formation, discussed the role of epigenetic changes in tumor formation. To study the potential benefits and risks of therapeutic agents that target DNMT enzymes, his group has been assessing the consequences of methylation changes on tumor incidence in different tissues. In addition to the increased methylation of certain tumor suppressor genes associated with colorectal and bladder cancers, genomewide DNA hypomethylation can occur in many human cancers. It has not, however, been determined whether this epigenetic change is a cause or consequence of tumorigenesis.

Jaenisch's group generated mice in which expression of DNMT-1 was reduced to 10% of wild-type levels. This resulted in substantial genomewide hypomethylation in all tissues. By 4-8 months of age, the mice developed aggressive T-cell lymphomas displaying a high frequency of chromosome 15 trisomies. So, a reduction in the level of DNA methylation can actually cause tumor formation, possibly by promoting chromosomal instability. The development of lymphoma was also seen in mice with mutations that downregulated DNMT-1 expression and that were treated with 5-aza-2'-deoxycytidine. Conversely, other studies have shown a correlation between increased DNMT-1 levels and intestinal tumor formation in mice.

These disparate findings indicate that DNMT activity can either promote or inhibit cancer, depending on the tissue type, thus warning that drugs targeted to these enzymes should be tested with great caution.

But what about the safety of drugs that alter histone acetylation? John Byrd,[7] of The Ohio State University, Columbus, discussed the potential use of HDAC inhibitors to treat patients with hematologic malignancies. He is studying the effects of the HDAC inhibitor depsipeptide (FK228), which has been shown to promote histone hyperacetylation, gene re-expression, and apoptosis in chronic lymphocytic leukemia (CLL) and AML cells. His group performed a minimum effective pharmacologic dose study of depsipeptide to identify the concentration of this drug at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro.

In a phase 1 study, 10 patients with CLL and 10 patients with AML were treated with 13 mg/m2 of depsipeptide intravenously on days 1, 8, and 15 of therapy. Several patients had evidence of antitumor activity following treatment, but no complete responses were observed. Evidence of tumor-cell lysis was present in 1 patient with AML, and a partial response was seen in 1 patient with CLL. Seven patients with CLL also had improved peripheral lymphocyte counts. Most patients, however, experienced progressive fatigue, nausea, and other symptoms that prevented repeated therapy. No life-threatening effects were reported.

Treatment was associated with HDAC inhibition and an increase in histone acetylation of at least 100% in cancer cells isolated from the patients and an increase in acetylation of histones associated with the p21 promoter. This led to increased expression of the p21 protein and the antigen 1D10. So, the drug depsipeptide effectively inhibited HDAC activity in patients with CLL and AML, but its use was limited by its side effects. Future studies will evaluate whether alternative administration schedules may improve tolerance to this drug in cancer patients.

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