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01.01.2013 | Original Article

Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer

verfasst von: B. F. Chu, M. J. Karpenko, Z. Liu, J. Aimiuwu, M. A. Villalona-Calero, K. K. Chan, M. R. Grever, G. A. Otterson

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2013

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Abstract

Purpose

Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC.

Methods

We performed a phase I trial combining 5-aza-2′-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5–15 mg/m²) IV for 10 days in combination with VPA (10–20 mg/kg/day) PO on days 5–21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression.

Results

Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0–2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results.

Conclusions

We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further.

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346(2):92–98. doi:10.1056/NEJMoa011954 PubMedCrossRef

Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19(13):3210–3218PubMed

Bertino EM, Otterson GA (2010) Benefits and limitations of antiangiogenic agents in patients with non-small cell lung cancer. Lung Cancer 70(3):233–246. doi:10.1016/j.lungcan.2010.08.018 PubMedCrossRef

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139. doi:10.1056/NEJMoa040938 PubMedCrossRef

Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160–1174. doi:10.1056/NEJMra0707704 PubMedCrossRef

Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734. doi:10.1038/nrc3130 PubMedCrossRef

Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. doi:10.1016/j.cell.2007.01.029 PubMedCrossRef

Schrump DS, Nguyen DM (2005) Targeting the epigenome for the treatment and prevention of lung cancer. Semin Oncol 32(5):488–502. doi:10.1053/j.seminoncol.2005.07.007 PubMedCrossRef

Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610. doi:10.1038/nrg1655 PubMedCrossRef

10.

Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6(2):107–116. doi:10.1038/nrc1799 PubMedCrossRef

11.

Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2′-deoxycytidine (decitabine). Semin Oncol 32(5):443–451. doi:10.1053/j.seminoncol.2005.07.008 PubMedCrossRef

12.

Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27(32):5459–5468. doi:10.1200/JCO.2009.22.1291 PubMedCrossRef

13.

Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, Hancox A, Hong JA, Chen GA, Kruchin E, Wright JJ, Rosing DR, Sparreboom A, Figg WD, Steinberg SM (2008) Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res 14(1):188–198. doi:10.1158/1078-0432.CCR-07-0135 PubMedCrossRef

14.

Zhu WG, Otterson GA (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents 3(3):187–199PubMedCrossRef

15.

Marchion D, Munster P (2007) Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther 7(4):583–598. doi:10.1586/14737140.7.4.583 PubMedCrossRef

16.

Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21(1):103–107. doi:10.1038/5047 PubMedCrossRef

17.

Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741. doi:10.1074/jbc.M101287200 PubMedCrossRef

18.

Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, Gonzalez-Fierro A, Chavez-Blanco A, de la Cruz-Hernandez E, Camargo MF, Trejo-Becerril C, Perez-Cardenas E, Perez-Plasencia C, Taja-Chayeb L, Wegman-Ostrosky T, Revilla-Vazquez A, Duenas-Gonzalez A (2007) A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 18(9):1529–1538. doi:10.1093/annonc/mdm204 PubMedCrossRef

19.

Koshy M, Dorn L, Bressler L, Molokie R, Lavelle D, Talischy N, Hoffman R, van Overveld W, DeSimone J (2000) 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 96(7):2379–2384PubMed

20.

Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD (2001) Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61(1):249–255PubMed

21.

Lin J, Gilbert J, Rudek MA, Zwiebel JA, Gore S, Jiemjit A, Zhao M, Baker SD, Ambinder RF, Herman JG, Donehower RC, Carducci MA (2009) A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clinical Cancer Res 15(19):6241–6249. doi:10.1158/1078-0432.CCR-09-0567 CrossRef

22.

Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’Brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108(10):3271–3279. doi:10.1182/blood-2006-03-009142 PubMedCrossRef

23.

Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25(25):3884–3891. doi:10.1200/JCO.2006.09.4169 PubMedCrossRef

24.

Oki Y, Aoki E, Issa JP (2007) Decitabine–bedside to bench. Crit Rev Oncol Hematol 61(2):140–152. doi:10.1016/j.critrevonc.2006.07.010 PubMedCrossRef

25.

Oki Y, Issa JP (2007) Treatment options in advanced myelodysplastic syndrome, with emphasis on epigenetic therapy. Int J Hematol 86(4):306–314. doi:10.1532/IJH97.07034 PubMedCrossRef

26.

Hurtubise A, Momparler RL (2006) Effect of histone deacetylase inhibitor LAQ824 on antineoplastic action of 5-Aza-2′-deoxycytidine (decitabine) on human breast carcinoma cells. Cancer Chemother Pharmacol 58(5):618–625. doi:10.1007/s00280-006-0225-6 PubMedCrossRef

27.

Atadja P, Gao L, Kwon P, Trogani N, Walker H, Hsu M, Yeleswarapu L, Chandramouli N, Perez L, Versace R, Wu A, Sambucetti L, Lassota P, Cohen D, Bair K, Wood A, Remiszewski S (2004) Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824. Cancer Res 64(2):689–695PubMedCrossRef

28.

Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, Grever M, Galm O, Dauses T, Karp JE, Rudek MA, Zhao M, Smith BD, Manning J, Jiemjit A, Dover G, Mays A, Zwiebel J, Murgo A, Weng LJ, Herman JG (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66(12):6361–6369. doi:10.1158/0008-5472.CAN-06-0080 PubMedCrossRef

29.

Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, Hancox A, Hong JA, Chen GA, Pishchik V, Figg WD, Murgo AJ, Steinberg SM (2006) Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res 12(19):5777–5785. doi:10.1158/1078-0432.CCR-06-0669 PubMedCrossRef

30.

Otterson GA, Hodgson L, Pang H, Vokes EE (2010) Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304). J Thorac Oncol 5(10):1644–1648. doi:10.1097/JTO.0b013e3181ec1713 PubMedCrossRef

31.

Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner LA, McGill S, Wang L, Zhang WJ, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17(6):1582–1590. doi:10.1158/1078-0432.CCR-10-1893 PubMedCrossRef

Titel: Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer
verfasst von: B. F. Chu
M. J. Karpenko
Z. Liu
J. Aimiuwu
M. A. Villalona-Calero
K. K. Chan
M. R. Grever
G. A. Otterson
Publikationsdatum: 01.01.2013
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2013
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1986-8

Springer Medizin

Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer