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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 1955-1956 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.8293
Addition of Histone Deacetylase Inhibitors in Combination TherapyThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD Our understanding of the biology of cancer has undoubtedly improved in the last decade. Although remarkable progress has been achieved in the treatment of cancer, much remains to be learned about the delivery of therapeutic agents, particularly with regard to the optimal combination and timing of biologic agents with cytotoxic therapy. Not long ago, the more is better strategy exemplified by high-dose chemotherapy (often resulting in increased toxicity) dominated the research agenda and clinical practices. With the option of biologically targeted therapy, novel agents have driven innovation on the accurate measurement of clinical responses and relevant biologic parameters. Current use of agents targeting epigenetic changes exemplifies this trend in clinical research. Encouraging response rates in patients receiving agents that target epigenetic marks drives continued efforts to identify key laboratory correlates that might help to deliver drugs in an optimal manner and to identify the key biologic features to elucidate a more exact mechanism of action. Histone deacetylase (HDAC) inhibitors represent some of the most promising epigenetic treatments for cancer because they have been proven to reactivate silenced genes and have pleiotropic antitumor effects selectively in cancer cells.1 The acetylation state of histones is reversibly regulated by two sets of enzymes, histone acetyltransferases (HATs) and HDACs. The activity of these two enzymes regulates, in part, the chromatin architecture; HAT is associated with the transcriptionally active state (euchromatin), and HDAC is associated with the transcriptionally repressed state (heterochromatin).2 The recruitment of HDAC by DNA methyltransferase and by specific methyl-binding proteins represses transcription by inducing a transcriptionally repressed state of chromatin.3 Acetylation of the histone can be mediated by multiprotein complexes containing HATs along with inhibition of HDAC activity. Acetylation neutralizes the positive charge associated with the amino group on conserved lysine residues in the histone tails, thereby facilitating access of a variety of factors to DNA. HDACs are also involved in the regulation of biologic functions including cell growth, differentiation, and oncogenesis. HDAC inhibitors have shown promising significant in vitro and in vivo activity against a variety of hematologic and solid tumor model systems.4,5 HDAC inhibitors, such as valproic acid (VPA), vorinistat, MS-275, FK228, sodium phenylbutyrate, and others, hinder HDACs with varying degrees of class specificity and directly result in histone hyperacetylation with potential facilitation to the euchromatic state. This mediates a consequent increase in tumor suppressor gene re-expression and may explain part of the anticancer effect of these agents. Active investigation is ongoing to evaluate combinations of HDAC inhibitors with DNA methyltransferase inhibitors such as azacitidine to enhance gene re-expression and clinical activity. Combining these agents with cytotoxic therapy is a rational progression because treatment with an HDAC inhibitor will offer improved access for cytotoxic agents to the target DNA/protein complex.6 Several preclinical reports have shown that HDAC inhibitors synergize with cytotoxic agents, such as DNA topoisomerase II inhibitors,6-9 taxanes,10 and mitomycin,11 as well as biologic agents, such as imatinib12 and gemtuzumab.13 These studies involve combination treatment of many cancer cell lines, including acute leukemia and colon, breast, endometrial, and thyroid cancer cell lines, and demonstrate the potential impact that inhibiting HDACs can have across all cancer types. When combining agents, the sequence of their delivery may have a profound impact on outcome. In xenograft models, as well as in vitro, synergistic induction of cell death by VPA pretreatment before topoisomerase II inhibitor administration was abrogated when VPA was administered concurrent with or after the topoisomerase II inhibitor.14 Another challenging aspect in approaching the combination of biologic and cytotoxic therapy is identifying the optimal doses for combination and whether this should be identified as the traditional maximum-tolerated dose (MTD) or as the optimal biologic dose. This challenge faces delivery of many current novel cancer regimens and is being addressed in innovative clinical trial designs. In the case of DNA methyltransferase inhibitors and HDAC inhibitors, a variety of studies suggest that lower doses may lead to superior reversal of methylation and potentially result in improved clinical outcome. Examples of this are improved responses seen in patients with hematologic diseases receiving lower doses of demethylating agents like azacitidine with or without HDAC inhibitors15,16 and the statistically significant reduction of prostate tumor growth observed in a xenograft model after treatment with a chronic low-dose HDAC inhibitor, independent of androgen regulation.17 The article in this issue by Münster et al18 is an important contribution to the clinical understanding of the role of HDAC inhibitors in combination therapy for solid tumors. This phase I study administered escalating doses of the HDAC inhibitor VPA on days 1 through 3 with epirubicin on days 3 to 44 in patients with solid tumor malignancies. Although histone acetylation was seen in the peripheral mononuclear cells after patients received VPA, increasing the VPA dose to the MTD did not seem to increase clinical response rate or significantly increase histone acetylation. However, this combination therapy led to exciting clinical responses in an otherwise refractory population. Other studies have shown similar findings. The combination of 5-AZA-2'-deoxycytidine and VPA showed a 22% overall response rate in patients with acute leukemia, although no relationship was observed between histone acetylation and VPA levels.19 Thus, revisiting the idea that the MTD may not represent the optimal dose may impact our ability to identify the ideal drug combination with improved efficacy and tolerability as a biologic agent. These concepts may lead to improved patient compliance as a result of decreased adverse effects as well as to decreased overall medical expenditures associated with lower doses of novel biologic agents. Lower doses might also reduce associated toxicity and be useful in avoiding drug resistance. Determining the optimal order of agents, dose, and route of administration and accurately defining metrics of biologic activity in conjunction with clinical responses are some of the most Herculean aspects of adequately developing any of these novel therapies. In the case of promising clinical combinations, the ultimate question of superiority to single-agent therapy must be asked. In the phase I study by Münster et al,18 impressive responses were seen in patients with otherwise refractory melanoma, breast, cervical, prostate, and small-cell lung cancer. Could the observed responses be entirely explained by single-agent epirubicin? Single-agent epirubicin has elicited an overall response rate of 48% in patients with metastatic breast cancer, although patients in that particular study were naïve to anthracyclines or any adjuvant chemotherapy.20 Single-agent epirubicin is not effective in patients with melanoma and colorectal cancer, which would further support efficacy of the combination with VPA.21 If laboratory correlates suggest exciting in vivo biologic activity, what is the best approach to optimize dosing and continue trial design if the clinical data seem similar to single-agent therapy? Clinical trials demonstrate that HDAC inhibitors are well tolerated and show objective single-agent responses in solid and hematologic malignancies. A more detailed understanding of the molecular basis behind their antitumor activity is crucial. Translational studies are required to correlate histone acetylation, gene transcription, and tumor response, as well as nonepigenetic mechanisms including induction of reactive oxygen species, acetylation of HSP90, and impact on tumor necrosis factor–related apoptosis-inducing ligand receptors and nuclear factor-kappa ß signaling.1 It is essential to determine optimal therapeutic doses, timing, and mode of administration of these agents. The study by Münster et al18 is the first clinical study in which combination therapy of VPA and epirubicin is administered to patients with solid tumors and deals with the hard issues in addressing the efficacy of both clinical and biologic mechanisms. This is an exciting time to be involved in combining agents for cancer therapy, and it is of utmost importance for clinicians and scientists to take on the challenge of optimizing delivery of these novel agents. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Hetty E. Carraway, Steven D. Gore Collection and assembly of data: Hetty E. Carraway Data analysis and interpretation: Hetty E. Carraway Manuscript writing: Hetty E. Carraway, Steven D. Gore Final approval of manuscript: Hetty E. Carraway, Steven D. Gore REFERENCES 1. Rosato RR, Grant S: Histone deacetylase inhibitors: Insights into mechanisms of lethality. Expert Opin Ther Targets 9: 809-824, 2005[CrossRef][Medline] 2. Marks P, Rifkind RA, Richon VM, et al: Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer 1: 194-202, 2001[CrossRef][Medline] 3. Robertson KD, Ait-Si-Ali S, Yokochi T, et al: DNMT1 forms a complex with rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25: 338-342, 2000[CrossRef][Medline] 4. Sambucetti LC, Fischer DD, Zabludoff S, et al: Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects. J Biol Chem 274: 34940-34947, 1999 5. Kosugi H, Towatari M, Hatano S, et al: Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: A new approach to anti-leukemia therapy. Leukemia 13: 1316-1324, 1999[CrossRef][Medline] 6. Marchion DC, Bicaku E, Daud AI, et al: Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92: 223-237, 2004[CrossRef][Medline] 7. Catalano MG, Fortunati N, Pugliese M, et al: Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. J Endocrinol 191: 465-472, 2006 8. Kurz EU, Wilson SE, Leader KB, et al: The histone deacetylase inhibitor sodium butyrate induces DNA topoisomerase II alpha expression and confers hypersensitivity to etoposide in human leukemic cell lines. Mol Cancer Ther 1: 121-131, 2001 9. Tsai SC, Valkov N, Yang WM, et al: Histone deacetylase interacts directly with DNA topoisomerase II. Nat Genet 26: 349-353, 2000[CrossRef][Medline] 10. Dowdy SC, Jiang S, Zhou XC, et al: Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Mol Cancer Ther 5: 2767-2776, 2006 11. Friedmann I, Atmaca A, Chow KU, et al: Synergistic effects of valproic acid and mitomycin C in adenocarcinoma cell lines and fresh tumor cells of patients with colon cancer. J Chemother 18: 415-420, 2006[Medline] 12. Nimmanapalli R, Fuino L, Stobaugh C, et al: Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of bcr-abl-positive human acute leukemia cells. Blood 101: 3236-3239, 2003 13. Ten Cate B, Samplonius DF, Bijma T, et al: The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia 21: 248-252, 2007[CrossRef][Medline] 14. Marchion DC, Bicaku E, Daud AI, et al: In vivo synergy between topoisomerase II and histone deacetylase inhibitors: Predictive correlates. Mol Cancer Ther 4: 1993-2000, 2005 15. Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109: 52-57, 2007 16. Gore SD, Baylin S, Sugar E, et al: Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66: 6361-6369, 2006 17. Xia Q, Sung J, Chowdhury W, et al: Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. Cancer Res 66: 7237-7244, 2006 18. Münster P, Marchion D, Bicaku E, et al: Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: A clinical and translational study. J Clin Oncol 25: 1979-1985, 2007 19. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al: Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 108: 3271-3279, 2006 20. Michelotti A, Venturini M, Tibaldi C, et al: Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Breast Cancer Res Treat 59: 133-139, 2000[CrossRef][Medline] 21. Rosenthal MA, Green M, Wiernik P, et al: Epirubicin has modest single-agent activity in head and neck cancer but limited activity in metastatic melanoma and colorectal cancer: Phase II studies by the eastern cooperative oncology group. Am J Clin Oncol 21: 509-512, 1998[CrossRef][Medline]
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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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