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Pancreatic Cancer pp 1551–1575Cite as

Epigenetic Pharmacology

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Abstract

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.

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References

  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: http://seer.cancer.gov/csr/1975_2013/. Accessed July 2016.

  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. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.

    Article  CAS  Google Scholar 

  4. Ahuja N, Sharma AR, Baylin SB. Epigenetic therapeutics: a new weapon in the war against cancer. Annu Rev Med. 2016;67:73–89.

    Article  CAS  Google Scholar 

  5. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447(7143):425–32.

    Article  CAS  Google Scholar 

  6. Baylin SB, Jones PA. A decade of exploring the cancer epigenome – biological and translational implications. Nat Rev Cancer. 2011;11(10):726–34.

    Article  CAS  Google Scholar 

  7. Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev. 2012;22(1):50–5.

    Article  CAS  Google Scholar 

  8. Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 2016;8:9–21.

    Article  Google Scholar 

  9. Millan MJ. An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology. 2013;68:2–82.

    Article  CAS  Google Scholar 

  10. Kim HS, Minna JD, White MA. GWAS meets TCGA to illuminate mechanisms of cancer predisposition. Cell. 2013;152(3):387–9.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  20. Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010;11(3):204–20.

    Article  CAS  Google Scholar 

  21. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10(5):295–304.

    Article  CAS  Google Scholar 

  22. Prokhortchouk E, Defossez PA. The cell biology of DNA methylation in mammals. Biochim Biophys Acta. 2008;1783(11):2167–73.

    Article  CAS  Google Scholar 

  23. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  28. Silverman LR, Mufti GJ. Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat Clin Pract Oncol. 2005;2(Suppl 1):S12–23.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  38. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  42. Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12(12):917–30.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  47. Robert C, Rassool FV. HDAC inhibitors: roles of DNA damage and repair. Adv Cancer Res. 2012;116:87–129.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  52. Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 2004;3(6):779–88.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  62. Fortschegger K, Shiekhattar R. Plant homeodomain fingers form a helping hand for transcription. Epigenetics. 2011;6(1):4–8.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  65. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.

    Article  CAS  Google Scholar 

  66. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  70. Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012;2(3):214–26.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 611, Baltimore, MD, 21287, USA

    Richard A. Burkhart

  2. Department of Surgery, Johns Hopkins University, Cancer Research Building 1, Baltimore, MD, 21287, USA

    Anup R. Sharma

  3. Department of Surgery, Division of Surgical Oncology, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 685, Baltimore, MD, 21287, USA

    Nita Ahuja

Authors
  1. Richard A. Burkhart
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  2. Anup R. Sharma
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  3. Nita Ahuja
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Corresponding author

Correspondence to Richard A. Burkhart .

Editor information

Editors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    John P. Neoptolemos

  2. Division of Research Department of Surgery and Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Raul Urrutia

  3. Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    James L. Abbruzzese

  4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Markus W. Büchler

Section Editor information

  1. Division of Surgery and Oncology, University of Liverpool, Daulby Street, Liverpool, UK

    John Neoptolemos

  2. Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Raul A. Urrutia

  3. Duke University Medical Center, Durham, NC, USA

    James L. Abbruzzese

  4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Markus W. Büchler

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Burkhart, R.A., Sharma, A.R., Ahuja, N. (2018). Epigenetic Pharmacology. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7193-0_69

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