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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4519-4521 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.6029
Combining Epigenetic and Cytotoxic Therapy in the Treatment of Solid TumorsThe University of Texas M.D. Anderson Cancer Center, Houston, Texas DNA methylation is a clonally inherited mechanism of gene silencing that occurs when a methyl group becomes covalently attached to the 5-carbon position of a cytosine residue at a "CpG" site. This epigenetic process occurs during S phase and is catalyzed by the DNA methyltransferase (DNMT) family of enzymes.1,2 Genes with heavily methylated promoter regions cannot be transcribed and are effectively silenced. In cancer cells, many genes, including tumor suppressor genes, are abnormally silenced by DNA methylation. In addition to potentially modulating cancer biology, DNA methylation and associated silencing has been shown to be involved in the development of drug resistance,3 prompting investigations of the use of hypomethylation therapy to resensitize malignant cells to classical cytotoxic agents. The flattening of the dose-response curve at higher drug doses for many cytotoxic agents suggests that downregulation of expression of factors required for tumor cell killing may be at least as important as overexpression of resistance factors in limiting the ability to cure advanced epithelial tumors.4 Decitabine is a cytosine analog that is a powerful hypomethylating agent, especially at lower doses.5 Previous studies have shown that DNA in treated cells becomes progressively hypomethylated after each round of transcription in the presence of decitabine.6 Gene-specific hypomethylation by decitabine may be responsible for the reactivation of tumor suppressor genes and tumor antigens that are frequently silenced by methylation in neoplasia.7-12 Decitabine has shown significant promise in the treatment of hematopoietic malignancies, and is an approved therapy for the treatment of myelodysplastic syndrome (MDS).13 Its track record in solid tumors has been less impressive. During the last two decades, a handful of clinical trials investigating the use of decitabine in solid tumors have reported high toxicity, particularly myelosuppression, and meager response rates.12,14,15 Trials investigating the combination of decitabine with cisplatin in solid tumors have been similarly disappointing.16,17 However, it is important to note that the majority of these studies used dose and schedule combinations that are now recognized to be suboptimal. Clinical observations in MDS have shown that low-dose but high-intensity, multiday, and multicycle administration are all key factors in achieving responses to decitabine.7 The reported solid tumor trials generally used higher, more toxic doses of decitabine, single day administration for one cycle only, and, in the case of combination therapy, concurrent administration of decitabine with cytotoxic agents. Several years ago, Plumb et al3 showed that resistance to carboplatin in ovarian cancer cells was mediated by hypermethylation and loss of function of the MLH1 mismatch repair gene, and that decitabine resensitized the cells to the platinum compound through hypomethylation induction. In this issue of the Journal of Clinical Oncology, Appleton et al18 test this concept in a trial combining decitabine and carboplatin in advanced solid tumors. This dose-finding trial uses a series of doses of decitabine that, per cycle, all fall within the range of low doses shown to induce hypomethylation in vitro and in vivo. Furthermore, decitabine was administered 8 days before initiation of cytotoxic therapy, in keeping with preclinical models.3,19 The investigators conducted two separate dose escalations of decitabine, the first with carboplatin fixed at area under the concentration time curve (AUC) 5 and the second at AUC 6, concluding that the recommended phase II dosing for this combination is decitabine 90 mg/m2 administered on day 1 followed by carboplatin AUC 6 on day 8 of a 28-day cycle. Of the 30 patients assessable for response, one patient with melanoma had a partial response and three other patients had stable disease. The majority of responses clustered at the recommended combination dose. A strength of the current report resides in the careful correlative studies. DNA from peripheral-blood mononuclear cells (PBMCs), buccal cells, and tumor tissue was assessed for changes in DNA methylation and gene expression. Consistent with previous studies,20,21 hypomethylation in PBMCs was most pronounced in the middle of the cycle. Of some concern, methylation rapidly recovered to baseline by day 20. In studies where decitabine was administered for 5 to 10 days per cycle, recovery did not happen until after day 30,20,21 affording a longer therapeutic window for hypomethylation. Also, prior studies have shown a continued linear increase in methylation nadirs as decitabine dose was titrated up to 200 mg/m2/cycle, a dose that could not be reached in this study because of toxicity.22 This may or may not be relevant in light of the fact that, to date, the degree of hypomethylation in PBMCs has not been shown to correlate with disease response; therefore, pushing decitabine to the high end of the low-dose spectrum may not be important.21 Moreover, what has been shown to be correlated with response in clinical trials in MDS is the number of cycles of decitabine administered. This finding may be explained by the accumulation of hypomethylated genes after repeated decitabine administration.21,23 Supporting this theory, data from the current study show that fetal hemoglobin, normally silenced in adults, accumulates with increased cycles of decitabine treatment. Therefore, keeping toxicity low to allow for repeated dosing may be more important than deepening the nadir of methylation in each cycle. In this study, Appleton et al present, for the first time, a comparison between the methylation of surrogate, normal, and tumor tissue. It is interesting, though not surprising, that tumor tissue shows significantly less hypomethylation after decitabine treatment than do surrogate tissues such as PBMCs and buccal cells. There are a variety of reasons that tumor uptake of antineoplastic agents may be impaired. Substantial attention has been paid to the potential role of altered tumor vascularity and increased tissue pressure.24,25 In addition, variability in extracellular pH across different regions of tumor could affect uptake, because drugs that are weak acids are preferentially taken up into tumors with lower pH and are more active in such tumors, whereas drugs that are weak bases have increased uptake and cytotoxicity in tumors with higher pH.26 Moreover, tumors that are resistant to platinums may have a pleiotropic reduction in uptake of multiple drugs and nutrients, with a reduction and mislocalization of membrane proteins and impaired endocytosis.27 This could lead to resistance through impaired drug uptake, but it is also associated with reduced tumor growth rate,27 and the reduced proliferation rate could potentially result in lower DNA incorporation of decitabine, an S-phase–specific agent. Of interest, decitabine reverses the downregulation of expression of some membrane transporters in vitro,28 raising the untested possibility that repeated treatment could lead to a progressive increase in efficacy. Although it is unknown whether the major issue involves either drug uptake or tumor cell proliferation rate, tumor biopsies showed a disappointingly small decrease of methylation (3%), which was below the threshold for resensitization to chemotherapy in preclinical studies.3 This finding underscores the pitfalls inherent in using surrogate tissues to monitor molecular response to decitabine and highlights the challenges in developing hypomethylating agents in solid tumors. Is this combination ready for prime-time testing? This question is mostly rhetorical, given that a separate phase II trial of decitabine and carboplatin in ovarian cancer is ongoing. However, given the poor track record of decitabine in solid tumors so far, it would appear wise to carefully consider the optimal dose of the agent in solid tumors before proceeding much further. In line with data in MDS, it could be helpful to test the effects of longer exposure to decitabine (several days/cycle, several cycles) on hypomethylation induction in malignant tissues in vitro and in vivo. Also, given that myelosuppression is associated with both decitabine and carboplatin, it may be of interest to test cisplatin instead. One issue to consider in future dose finding trials of such combination therapies is the possibility of a more efficient clinical trial design. In the current study, the investigators used two separate dose escalation cohorts to arrive at the maximum-tolerated dose (MTD), which they put forth as the recommended phase II dose. A separate phase II trial is ongoing to assess efficacy. This traditional two-phase design uses a large number of patients, many of whom are likely to be treated at suboptimal doses. Furthermore, the first phase is designed to select only for the MTD, without taking efficacy into consideration. As we have learned from studying decitabine in hematologic malignancies, the MTD may not be the optimum therapeutic dose, especially if cumulative toxicity limits the total number of cycles administered. One alternate design recently proposed for such combinations is a parallel phase I/II trial design.29 With this strategy, the dose of either agent is increased in parallel arms until the MTD is reached. Subsequent patients are adaptively randomly assigned to all admissible dose levels. In this way, all tolerated doses are assessed for efficacy until one dose combination emerges as both tolerated and most efficacious. Although not powered to determine a statistically significant difference between dose levels, this design allows for the use of efficacy data in addition to toxicity data in determining the recommended dose for future investigations. Other benefits to this design include expedited accrual because patients are entered at multiple dose levels concurrently; furthermore, this design should be more appealing to patients because they can expect to be preferentially randomly assigned to the most efficacious dose combination. Exploiting gene reactivation by epigenetic acting agents in combination with cytotoxic therapies is a strategy that holds much clinical promise. Appleton et al18 report in this issue of the Journal a dose-finding trial based on a preclinical xenograft model, and have selected what appears to be appropriate (though perhaps not optimal) combination dosing. It will be interesting to see what results can be achieved using this combination in pretreated patients with ovarian cancer, as the investigators have planned. It is possible that the overlapping toxicities of the two drugs, particularly myelosuppression, may preclude safe administration of the number of cycles needed to achieve response, especially in heavily pretreated patients. However, it is also possible that results in humans might be significantly more robust than those noted in nude mouse xenografts on the basis of effects that cannot be appropriately modeled in mice, such as immunologic synergy related to the upregulation of tumor antigens such as MAGE as shown in this phase I study. In the age of genetic, epigenetic and targeted therapy, innovative clinical trial designs with strong, integrated, correlative science will also be key to moving cancer therapy forward. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure 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 in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jean-Pierre J. Issa, MGI Pharma (C), Pharmion (C) Stock Ownership: None Honoraria: Jean-Pierre J. Issa, MGI Pharma, Pharmion Research Funding: Jean-Pierre J. Issa, MGI Pharma, Pharmion Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Elizabeth R. Plimack, David J. Stewart, Jean-Pierre J. Issa Manuscript writing: Elizabeth R. Plimack, David J. Stewart, Jean-Pierre J. Issa Final approval of manuscript: Elizabeth R. Plimack, David J. Stewart, Jean-Pierre J. Issa REFERENCES
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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