Pancreatic Cancer pp 1551-1575 | Cite as

Epigenetic Pharmacology

  • Richard A. Burkhart
  • Anup R. Sharma
  • Nita Ahuja
Reference work entry


Decades of research focused on the genetic basis for development of pancreatic ductal adenocarcinoma have yielded tremendous discoveries. Clues to increase our understanding of the underlying biology of disease, the time along which the disease develops, and the potential vulnerabilities of disease are being elucidated daily. Alongside this genetically driven paradigm, researchers have uncovered the phenomenon of dramatically altered protein expression in the absence of an associated gene mutation. Through a mechanism termed epigenetics, the transcription and translation of genes can be dramatically altered by a variety of mechanisms including DNA methylation and histone modification. The fundamental concepts of epigenetics and major molecular agents that participate in setting the epigenome are reviewed herein. For each mechanism, the pharmacologic agents available for current use and the research underlying their approval are discussed. The potential impact of epigenetic pharmacology in pancreatic cancer is discussed in turn, and future directions of current research efforts are outlined.


Pancreatic ductal adenocarcinoma Epigenetics Epigenetic pharmacology DNA methylation Histone modification DNA methyltransferase DNA methyltransferase inhibitor Histone deacetylase inhibitors 


  1. 1.
    Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Altekruse S, et al. SEER cancer statistics review, 1975–2013. Bethesda: National Cancer Institute; 2016. Available at: Accessed July 2016.
  2. 2.
    Allis CD, Caparros M, Jenuwein T, Reinberg D. Epigenetics. 2nd ed. Cold Spring Harbor: CSH Press, Cold Spring Harbor Laboratory Press; 2015.Google Scholar
  3. 3.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.CrossRefGoogle Scholar
  4. 4.
    Ahuja N, Sharma AR, Baylin SB. Epigenetic therapeutics: a new weapon in the war against cancer. Annu Rev Med. 2016;67:73–89.CrossRefGoogle Scholar
  5. 5.
    Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447(7143):425–32.CrossRefGoogle Scholar
  6. 6.
    Baylin SB, Jones PA. A decade of exploring the cancer epigenome – biological and translational implications. Nat Rev Cancer. 2011;11(10):726–34.CrossRefGoogle Scholar
  7. 7.
    Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev. 2012;22(1):50–5.CrossRefGoogle Scholar
  8. 8.
    Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 2016;8:9–21.CrossRefGoogle Scholar
  9. 9.
    Millan MJ. An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology. 2013;68:2–82.CrossRefGoogle Scholar
  10. 10.
    Kim HS, Minna JD, White MA. GWAS meets TCGA to illuminate mechanisms of cancer predisposition. Cell. 2013;152(3):387–9.CrossRefGoogle Scholar
  11. 11.
    Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene. 1998;17(18):2413–7.CrossRefGoogle Scholar
  12. 12.
    Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27–32.CrossRefGoogle Scholar
  13. 13.
    Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126–30.Google Scholar
  14. 14.
    Tan AC, Jimeno A, Lin SH, Wheelhouse J, Chan F, Solomon A, et al. Characterizing DNA methylation patterns in pancreatic cancer genome. Mol Oncol. 2009;3(5–6):425–38.CrossRefGoogle Scholar
  15. 15.
    Yi JM, Guzzetta AA, Bailey VJ, Downing SR, Van Neste L, Chiappinelli KB, et al. Novel methylation biomarker panel for the early detection of pancreatic cancer. Clin Cancer Res. 2013;19(23):6544–55.CrossRefGoogle Scholar
  16. 16.
    Easwaran H, Johnstone SE, Van Neste L, Ohm J, Mosbruger T, Wang Q, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res. 2012;22(5):837–49.CrossRefGoogle Scholar
  17. 17.
    Koenig A, Linhart T, Schlengemann K, Reutlinger K, Wegele J, Adler G, et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology. 2010;138(3):1189-99.e1-2.CrossRefGoogle Scholar
  18. 18.
    Patel JH, Loboda AP, Showe MK, Showe LC, McMahon SB. Analysis of genomic targets reveals complex functions of MYC. Nat Rev Cancer. 2004;4(7):562–8.CrossRefGoogle Scholar
  19. 19.
    Jones S, Li M, Parsons DW, Zhang X, Wesseling J, Kristel P, et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat. 2012;33(1):100–3.CrossRefGoogle Scholar
  20. 20.
    Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010;11(3):204–20.CrossRefGoogle Scholar
  21. 21.
    Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10(5):295–304.CrossRefGoogle Scholar
  22. 22.
    Prokhortchouk E, Defossez PA. The cell biology of DNA methylation in mammals. Biochim Biophys Acta. 2008;1783(11):2167–73.CrossRefGoogle Scholar
  23. 23.
    Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26.CrossRefGoogle Scholar
  24. 24.
    Riggs AD, Xiong Z, Wang L, LeBon JM. Methylation dynamics, epigenetic fidelity and X chromosome structure. Novartis Found Symp. 1998;214:214–225. discussion 225–32.Google Scholar
  25. 25.
    Gros C, Fahy J, Halby L, Dufau I, Erdmann A, Gregoire JM, et al. DNA methylation inhibitors in cancer: recent and future approaches. Biochimie. 2012;94(11):2280–96.CrossRefGoogle Scholar
  26. 26.
    Constantinides PG, Jones PA, Gevers W. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature. 1977;267(5609):364–6.CrossRefGoogle Scholar
  27. 27.
    Ahuja N, Easwaran H, Baylin SB. Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest. 2014;124(1):56–63.CrossRefGoogle Scholar
  28. 28.
    Silverman LR, Mufti GJ. Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat Clin Pract Oncol. 2005;2(Suppl 1):S12–23.CrossRefGoogle Scholar
  29. 29.
    Li A, Omura N, Hong SM, Goggins M. Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors. Cancer Biol Ther. 2010;9(4):321–9.CrossRefGoogle Scholar
  30. 30.
    Zhao G, Qin Q, Zhang J, Liu Y, Deng S, Liu L, et al. Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. Ann Surg Oncol. 2013;20(Suppl 3):S301–11.CrossRefGoogle Scholar
  31. 31.
    Zagorac S, Alcala S, Fernandez Bayon G, Bou Kheir T, Schoenhals M, Gonzalez-Neira A, et al. DNMT1 inhibition reprograms pancreatic cancer stem cells via upregulation of the miR-17-92 cluster. Cancer Res. 2016;76(15):4546–58.CrossRefGoogle Scholar
  32. 32.
    Kumari A, Srinivasan R, Wig JD. Effect of c-MYC and E2F1 gene silencing and of 5-azacytidine treatment on telomerase activity in pancreatic cancer-derived cell lines. Pancreatology. 2009;9(4):360–8.CrossRefGoogle Scholar
  33. 33.
    Shakya R, Gonda T, Quante M, Salas M, Kim S, Brooks J, et al. Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. Cancer Res. 2013;73(2):885–96.CrossRefGoogle Scholar
  34. 34.
    Nervi C, De Marinis E, Codacci-Pisanelli G. Epigenetic treatment of solid tumours: a review of clinical trials. Clin Epigenetics. 2015;7:127-015-0157-2. eCollection 2015.Google Scholar
  35. 35.
    Issa JP, Roboz G, Rizzieri D, Jabbour E, Stock W, O’Connell C, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099–110.CrossRefGoogle Scholar
  36. 36.
    Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol. 2007;18(9):1529–38.CrossRefGoogle Scholar
  37. 37.
    Saif MW, Tytler E, Lansigan F, Brown DM, Husband AJ. Flavonoids, phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary cancers. Exp Opin Investig Drugs. 2009;18(4):469–79.CrossRefGoogle Scholar
  38. 38.
    Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.CrossRefGoogle Scholar
  39. 39.
    Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA, et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2005;102(10):3697–702.CrossRefGoogle Scholar
  40. 40.
    Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13(9):673–91.CrossRefGoogle Scholar
  41. 41.
    Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014;123(5):697–705.CrossRefGoogle Scholar
  42. 42.
    Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12(12):917–30.CrossRefGoogle Scholar
  43. 43.
    Huang Y, Greene E, Murray Stewart T, Goodwin AC, Baylin SB, Woster PM, et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci U S A. 2007;104(19):8023–8.CrossRefGoogle Scholar
  44. 44.
    Riggs MG, Whittaker RG, Neumann JR, Ingram VM. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature. 1977;268(5619):462–4.CrossRefGoogle Scholar
  45. 45.
    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–40.CrossRefGoogle Scholar
  46. 46.
    Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P, et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med. 2005;11(1):77–84.CrossRefGoogle Scholar
  47. 47.
    Robert C, Rassool FV. HDAC inhibitors: roles of DNA damage and repair. Adv Cancer Res. 2012;116:87–129.CrossRefGoogle Scholar
  48. 48.
    West AC, Mattarollo SR, Shortt J, Cluse LA, Christiansen AJ, Smyth MJ, et al. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res. 2013;73(24):7265–76.CrossRefGoogle Scholar
  49. 49.
    Pili R, Salumbides B, Zhao M, Altiok S, Qian D, Zwiebel J, et al. Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Br J Cancer. 2012;106(1):77–84.CrossRefGoogle Scholar
  50. 50.
    Gupta P, Reid RC, Iyer A, Sweet MJ, Fairlie DP. Towards isozyme-selective HDAC inhibitors for interrogating disease. Curr Top Med Chem. 2012;12(14):1479–99.CrossRefGoogle Scholar
  51. 51.
    Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–9.CrossRefGoogle Scholar
  52. 52.
    Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 2004;3(6):779–88.CrossRefGoogle Scholar
  53. 53.
    Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H, Habtemariam BA, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666–70.CrossRefGoogle Scholar
  54. 54.
    Puvvada SD, Li H, Rimsza LM, Bernstein SH, Fisher RI, LeBlanc M, et al. A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520. Leuk Lymphoma. 2016;57(10):2359–69.CrossRefGoogle Scholar
  55. 55.
    Merino VF, Nguyen N, Jin K, Sadik H, Cho S, Korangath P, et al. Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer. Cancer Res. 2016;76(7):2013–24.CrossRefGoogle Scholar
  56. 56.
    Connolly RM, Zhao F, Miller K, Tevaarwerk A, Wagner LI, Lee M, et al. E2112: randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. J Clin Oncol. 2015;33(suppl:abstr):TPS636.Google Scholar
  57. 57.
    Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.CrossRefGoogle Scholar
  58. 58.
    Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598–607.CrossRefGoogle Scholar
  59. 59.
    Connolly RM, Jankowitz RC, Zahnow CA, Zhang Z, Rudek MA, Slater S, et al. Phase 2 study investigating the safety, efficacy, and surrogate biomarkers of response to 5-azacitidine (5-AZA) and entinostat in advanced breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(5s):569.Google Scholar
  60. 60.
    Kumagai T, Wakimoto N, Yin D, Gery S, Kawamata N, Takai N, et al. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. Int J Cancer. 2007;121(3):656–65.CrossRefGoogle Scholar
  61. 61.
    Arnold NB, Arkus N, Gunn J, Korc M. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances gemcitabine-induced cell death in pancreatic cancer. Clin Cancer Res. 2007;13(1):18–26.CrossRefGoogle Scholar
  62. 62.
    Fortschegger K, Shiekhattar R. Plant homeodomain fingers form a helping hand for transcription. Epigenetics. 2011;6(1):4–8.CrossRefGoogle Scholar
  63. 63.
    Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, et al. Functions of BET proteins in erythroid gene expression. Blood. 2015;125(18):2825–34.CrossRefGoogle Scholar
  64. 64.
    Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–73.CrossRefGoogle Scholar
  65. 65.
    Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.CrossRefGoogle Scholar
  66. 66.
    Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.CrossRefGoogle Scholar
  67. 67.
    Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature. 2008;451(7175):202–6.CrossRefGoogle Scholar
  68. 68.
    Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, et al. Antisense transcription in the mammalian transcriptome. Science. 2005;309(5740):1564–6.CrossRefGoogle Scholar
  69. 69.
    Gao W, Gu Y, Li Z, Cai H, Peng Q, Tu M, et al. miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene. 2015;34(13):1629–40.CrossRefGoogle Scholar
  70. 70.
    Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012;2(3):214–26.CrossRefGoogle Scholar
  71. 71.
    Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54(5):716–27.CrossRefGoogle Scholar
  72. 72.
    Qin L, Dong Z, Zhang JT. Reversible epigenetic regulation of 14-3-3sigma expression in acquired gemcitabine resistance by uhrf1 and DNA methyltransferase 1. Mol Pharmacol. 2014;86(5):561–9.CrossRefGoogle Scholar
  73. 73.
    Li Z, Liu JY, Zhang JT. 14-3-3sigma, the double-edged sword of human cancers. Am J Transl Res. 2009;1(4):326–40.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, et al. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012;72(9):2197–205.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Richard A. Burkhart
    • 1
  • Anup R. Sharma
    • 2
  • Nita Ahuja
    • 3
  1. 1.Department of Surgery, Division of Hepatobiliary and Pancreatic SurgeryJohns Hopkins HospitalBaltimoreUSA
  2. 2.Department of SurgeryJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of Surgery, Division of Surgical OncologyJohns Hopkins HospitalBaltimoreUSA

Section editors and affiliations

  • John Neoptolemos
    • 1
  • Raul A. Urrutia
    • 2
  • James L. Abbruzzese
    • 3
  • Markus W. Büchler
    • 4
  1. 1.Division of Surgery and OncologyUniversity of LiverpoolLiverpoolUK
  2. 2.Mayo Clinic Cancer CenterMayo ClinicRochesterUSA
  3. 3.Duke University Medical CenterDurhamUSA
  4. 4.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany

Personalised recommendations