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Making Bad Cells Go Good: The Promise of Epigenetic Therapy

Greenebaum Cancer Center, University of Maryland; and Johns Hopkins University, Baltimore MD

Among the prevailing explanations for the development of cancer over the past 50 years has risen the notion that clinically apparent cancers represent the failure of the tumor cells to differentiate along a pathway that would be expected for their tissues of origin. This point of view springs from and leads to the familiar characterization of epithelial neoplasms as well-, moderately, and poorly differentiated. This obviously orients our thinking about hematologic cancers, where the neoplastic cells frequently seem to be parodies of normal maturing marrow elements. Indeed, laboratory studies have demonstrated that exposure to various substances causes differentiation of certain hematopoietic tumor cells with their acquisition of more normal characteristics.

Historically, the field received a tremendous boost—and a challenge—when Leder and Leder¹ demonstrated that high concentrations of sodium butyrate could cause marked differentiation of murine erythroleukemia cells. The implications that profound regulation of gene expression could be manipulated by so simple a molecule had tantalizing mechanistic and therapeutic implications. The subsequent demonstration that high concentrations of sodium butyrate caused marked change in the acetylation state of histones pointed toward modification of DNA or chromatin-associated proteins as correlating with the basis for this effect.²

In parallel with these developments, longstanding observations that the methylation status of certain genes could influence their expression had arisen from the observations that there are actually five bases that could be detected in DNA. In addition to the familiar adenine, guanine, thymine, and cytosine, a variable proportion of cytosine existed as a methylated form. Moreover, the pattern of methylated cytosines was conserved from cycle to cycle of replication by the action of methyltransferases so that only one of the two chromosomes bearing certain genes was methylated. The methylated allele tended to be preferentially underexpressed. This nongenetic (in the sense that it did not arise from the sequence of the gene) but heritable feature was described as the mechanism "imprinting" certain maternally, as opposed to paternally, derived gene sets.³ Methylation was therefore regarded as an epigenetic way of regulating gene expression. The connection of DNA methylation status to tumor biology became appreciated by accumulating observations that while globally, tumors tend to have hypomethylated DNA, certain CPG islands could be defined, which become hypermethylated and thus prone to underexpression during oncogenesis.⁴

The confluence of these trains of investigation is that we can regard chromatin structure and DNA methylation status as legitimate sets of targets for the development of cancer therapeutics. Efforts to develop modulators of chromatin acetylation status and DNA modulation are the focus of this issue of the Journal of Clinical Oncology. The editors have strived to present a very up-to-the-moment "snap shot" of where the field is through the inclusion of both overview and clinical research reports. Melnick et al⁵ set the tone and pace by enlarging upon the concept that the regulation of transcription as an approach to cancer therapy can proceed by focusing on the increasingly numerous histone deacetylase (HDAC) family of enzymes, as well as potentially the histone acetylases and DNA methyltranferases as the basis for drug discovery. Bhalla,⁶ in turn, makes good on the promise afforded by the Leders' original observations by defining how, in the hematologic neoplasms, regulators of HDAC activity are already beginning to define noteworthy clinical phenomena. Both Dr Bhalla and Melnick et al place development in our growing understanding of the hematologic neoplasms as prominently highlighting deregulated transcription as a basis for neoplastic change, and therefore therapeutic opportunity.

Several "reductions to practice" of these theoretical underpinnings then occur. Kelly et al⁷ present phase I results of one of the flagship HDAC inhibitors in clinical development, suberoylanilide hydroxamic acid, and document its oral bioavailability and evidence of potential clinical benefit. Ryan et al⁸ likewise present phase I data on MS-275, an HDAC inhibitor of a distinct class, which also is being considered for further development. Samlowski et al⁹ present data supporting the idea that continuous infusions of low doses of 5'aza-2'deoxycytidine are capable of achieving clear modification of cytosine methylation status in surrogate tissues with little evidence of adverse effect. Rudek et al¹⁰ provide complementary data that in combination with phenylbutyrate, 5'azacytidine, while having the expected short half-life, can also on such brief schedules cause inhibition of DNA methyltransferase activity in patients' tumors.

Finally, several reports document aspects of epigenetic biology in chronic lymphocytic leukemia (Raval et al¹¹), diffuse large B-cell lymphomas (Agrelo et al¹²), acute promyelocytic leukemia (Bueso-Ramos et al¹³), and cutaneous T-cell lymphoma (van Doorn et al¹⁴), which continue to provide evidence that therapeutic tools to manipulate these targets would be of potential value in these disorders, or that diagnostic strategies incorporating an assessment of methylation or acetylation status of certain genes might provide useful prognostic information in approaching further clinical investigation efforts in these patients.

We therefore look forward to the continued progress of work in this area as the agents and diseases studied with modulators of epigenetic mechanisms increase. The focus of these efforts will be to evolve regimens to modulate tumor behavior by altering the very abnormal gene expression underlying neoplastic behavior itself. Major challenges remain. Will effects on normal tissues thwart this approach? Of the available HDAC inhibitors, are they expected to have the same effects on normal tissues, or will distinct effects emerge with the different agents? Should continuous or "pulsed" exposure to the agents be considered desirable? How many genes are being affected, and are they the same from tumor to tumor or tumor versus normal cells? All of these questions are just in the formative stages of being able to be asked. The articles in this issue will contribute to the basis for discussion and evolution of the field.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Edward A. Sausville, Schering AG; Michael A. Carducci, MethylGene, Curagen. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

REFERENCES

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2. Cousens LS, Gallwitz D, Alberts BM: Different accessibilites in chromatin to histone acetylase. J Biol Chem 254:1716-1723, 1979[Free Full Text]

3. Feinberg AP: DNA methylation, genomic imprinting and cancer. Curr Top Microbiol Immunol 249:87-99, 2000[Medline]

4. Rideout WM, Eversole-Cire P, Spruck CH, et al: Progressive increases in the methylation status and heterochromatinization of the myoD CpG island during oncogenic transformation. Mol Cell Biol 14:6143-6152, 1994[Abstract/Free Full Text]

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8. Ryan QC, Headlee D, Acharya M, et al: Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23: 10.1200/JCO.2005.02.188

9. Samlowski WE, Leachman SA, Wade M, et al: Evaluation of a 7-day continuous intravenous infusion of decitabine: Inhibition of promoter-specific and global genomic DNA methylation. J Clin Oncol 23: 10.1200/JCO.2005.06.118

10. Rudek MA, Zhao M, He P, et al: Pharmacokinetics of 5-azacitidine given with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J Clin Oncol 23: 10.1200/JCO.2005.07.450

11. Raval A, Lucas DM, Matkovic JJ, et al: TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia. J Clin Oncol 23: 10.1200/JCO.2005.02.196

12. Agrelo R, Setien F, Espada J, et al: Inactivation of the lamin A/C gene by CpG island promoter hypermethylation in hematologic malignancies, and its association with poor survival in nodal diffuse large B-cell lymphoma. J Clin Oncol 23: 10.1200/JCO.2005.11.650

13. Buesos-Ramos C, Xu Y, McDonnell TJ, et al: Protein expression of a triad of frequently methylated genes, p73, p57^Kip2, and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status. J Clin Oncol 23: 10.1200/JCO.2005.02.998

14. van Doorn R, Zoutman WH, Dijkman R, et al: Epigenetic profiling of cutaneous T-cell lymphoma: Promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 23: 10.1200/JCO.2005.11.353

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