Skip to main content

Advertisement

Log in

Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts

  • Review Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.

    Article  CAS  PubMed  Google Scholar 

  3. Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primer. 2016;2:16022.

    Article  Google Scholar 

  4. Pancreatic cancer incidence statistics. Cancer Research UK. 2015. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/incidence. Accessed 8 May 2016.

  5. Turati F, Edefonti V, Bosetti C, et al. Family history of cancer and the risk of cancer: a network of case-control studies. Ann Oncol Off J Eur Soc Med Oncol. 2013;24:2651–6.

    Article  CAS  Google Scholar 

  6. Bartsch DK, Kress R, Sina-Frey M, et al. Prevalence of familial pancreatic cancer in Germany. Int J Cancer. 2004;110:902–6.

    Article  CAS  PubMed  Google Scholar 

  7. Permuth-Wey J, Egan KM. Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Fam Cancer. 2009;8:109–17.

    Article  PubMed  Google Scholar 

  8. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Biankin AV, Maitra A. Subtyping pancreatic cancer. Cancer Cell. 2015;28:411–3.

    Article  CAS  PubMed  Google Scholar 

  10. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Neesse A, Algül H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut. 2015;64:1476–84.

    Article  CAS  PubMed  Google Scholar 

  12. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.

    Article  CAS  PubMed  Google Scholar 

  13. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003;17:3112–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bardeesy N, Aguirre AJ, Chu GC, et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA. 2006;103:5947–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bardeesy N, Cheng K-H, Berger JH, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Witkiewicz AK, McMillan EA, Balaji U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.

    Article  CAS  PubMed  Google Scholar 

  21. Moertel CG. Chemotherapy of gastrointestinal cancer. N Engl J Med. 1978;299:1049–52.

    Article  CAS  PubMed  Google Scholar 

  22. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.

    Article  CAS  PubMed  Google Scholar 

  23. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer. 2002;94:902–10.

    Article  CAS  PubMed  Google Scholar 

  24. Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010;28:1645–51.

    Article  CAS  PubMed  Google Scholar 

  25. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24:3946–52.

    Article  CAS  PubMed  Google Scholar 

  26. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–16.

    Article  CAS  PubMed  Google Scholar 

  27. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:3778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22:3776–83.

    Article  CAS  PubMed  Google Scholar 

  29. Stathopoulos GP, Syrigos K, Aravantinos G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006;95:587–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005;16:1639–45.

    Article  CAS  PubMed  Google Scholar 

  31. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25:2212–7.

    Article  CAS  PubMed  Google Scholar 

  32. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27:5513–8.

    Article  CAS  PubMed  Google Scholar 

  33. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996;7:548–57.

    Article  CAS  PubMed  Google Scholar 

  34. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31:1640–8.

    Article  CAS  PubMed  Google Scholar 

  35. O’Reilly EM. Evolving panorama of treatment for metastatic pancreas adenocarcinoma. J Clin Oncol. 2013;31:1621–3.

    Article  PubMed  CAS  Google Scholar 

  36. Sudo K, Nakamura K, Yamaguchi T. S-1 in the treatment of pancreatic cancer. World J Gastroenterol. 2014;20:15110–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cid-Arregui A, Juarez V. Perspectives in the treatment of pancreatic adenocarcinoma. World J Gastroenterol. 2015;21:9297–316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lemoine NR, Hughes CM, Barton CM, et al. The epidermal growth factor receptor in human pancreatic cancer. J Pathol. 1992;166:7–12.

    Article  CAS  PubMed  Google Scholar 

  39. Yamanaka Y, Friess H, Kobrin MS, et al. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res. 1993;13:565–9.

    CAS  PubMed  Google Scholar 

  40. Tobita K, Kijima H, Dowaki S, et al. Epidermal growth factor receptor expression in human pancreatic cancer: significance for liver metastasis. Int J Mol Med. 2003;11:305–9.

    CAS  PubMed  Google Scholar 

  41. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28:3605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.

    Article  CAS  PubMed  Google Scholar 

  43. Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13:3913–21.

    Article  CAS  PubMed  Google Scholar 

  44. Boeck S, Jung A, Laubender RP, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013;108:469–76.

    Article  CAS  PubMed  Google Scholar 

  45. Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12:256–62.

    Article  CAS  PubMed  Google Scholar 

  47. Rougier P, Riess H, Manges R, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 1990;2013(49):2633–42.

    Google Scholar 

  48. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    Article  CAS  PubMed  Google Scholar 

  49. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  CAS  Google Scholar 

  50. Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47:1676–81.

    Article  CAS  PubMed  Google Scholar 

  51. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32:2423–9.

    Article  CAS  PubMed  Google Scholar 

  52. Gill S, Ko Y-J, Cripps C, et al. PANCREOX: a randomized phase III study of 5-fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016; Sep 12. pii:JCO685776 [Epub ahead of print].

  53. Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545–57.

    Article  CAS  PubMed  Google Scholar 

  54. Boeck S, Wilkowski R, Bruns CJ, et al. Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer. Oncology. 2007;73:221–7.

    Article  CAS  PubMed  Google Scholar 

  55. Katopodis O, Polyzos A, Kentepozidis N, et al. Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. Cancer Chemother Pharmacol. 2011;67:361–8.

    Article  CAS  PubMed  Google Scholar 

  56. Soares HP, Bayraktar S, Blaya M, et al. A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere. Cancer Chemother Pharmacol. 2014;73:839–45.

    Article  CAS  PubMed  Google Scholar 

  57. Xiong HQ, Varadhachary GR, Blais JC, et al. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113:2046–52.

    Article  CAS  PubMed  Google Scholar 

  58. Berk V, Ozdemir N, Ozkan M, et al. XELOX vs. FOLFOX4 as second line chemotherapy in advanced pancreatic cancer. Hepatogastroenterology. 2012;59:2635–9.

    CAS  PubMed  Google Scholar 

  59. Xenidis N, Chelis L, Amarantidis K, et al. Docetaxel plus gemcitabine in combination with capecitabine as treatment for inoperable pancreatic cancer: a phase II study. Cancer Chemother Pharmacol. 2012;69:477–84.

    Article  CAS  PubMed  Google Scholar 

  60. Boeck S, Weigang-Köhler K, Fuchs M, et al. Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. Ann Oncol. 2007;18:745–51.

    Article  CAS  PubMed  Google Scholar 

  61. Oettle H, Arnold D, Esser M, et al. Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs. 2000;11:635–8.

    Article  CAS  PubMed  Google Scholar 

  62. Yoo C, Hwang JY, Kim J-E, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009;101:1658–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Teague A, Lim K-H, Wang-Gillam A. Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies. Ther Adv Med Oncol. 2015;7:68–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Teo MY, O’Reilly EM. Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer? J Gastrointest Oncol. 2016;7:738–49.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26:3785–90.

    Article  CAS  PubMed  Google Scholar 

  66. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8:2992–3000.

    Article  CAS  PubMed  Google Scholar 

  67. Aarts M, Sharpe R, Garcia-Murillas I, et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012;2:524–39.

    Article  CAS  PubMed  Google Scholar 

  68. Kausar T, Schreiber JS, Karnak D, et al. Sensitization of pancreatic cancers to gemcitabine chemoradiation by WEE1 kinase inhibition depends on homologous recombination repair. Neoplasia. 2015;17:757–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lal S, Zarei M, Chand SN, et al. WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner. Sci Rep. 2016;12(6):33323. doi:10.1038/srep33323.

    Article  CAS  Google Scholar 

  70. Venkatesha VA, Parsels LA, Parsels JD, et al. Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition. Neoplasia. 2012;14:519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Duong H-Q, Hong YB, Kim JS, et al. Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. J Cell Mol Med. 2013;17:1261–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dietlein F, Kalb B, Jokic M, et al. A synergistic interaction between Chk1- and MK2 inhibitors in KRAS-mutant cancer. Cell. 2015;162:146–59.

    Article  CAS  PubMed  Google Scholar 

  73. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen F, Wang W, El-Deiry WS. Current strategies to target p53 in cancer. Biochem Pharmacol. 2010;80:724–30.

    Article  CAS  PubMed  Google Scholar 

  75. Parrales A, Ranjan A, Iyer SV, et al. DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol. 2016;18:1233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Knudsen ES, O’Reilly EM, Brody JR, Witkiewicz AK. Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine. Gastroenterology. 2016;150:48–63.

    Article  PubMed  Google Scholar 

  77. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Friess H, Yamanaka Y, Büchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;105:1846–56.

    Article  CAS  PubMed  Google Scholar 

  80. Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.

    Article  CAS  PubMed  Google Scholar 

  81. Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov. 2012;11:790–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–7.

    Article  CAS  PubMed  Google Scholar 

  83. Stott FJ, Bates S, James MC, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17:5001–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tang B, Li Y, Qi G, et al. Clinicopathological significance of CDKN2A promoter hypermethylation frequency with pancreatic cancer. Sci Rep. 2015;5:13563.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Oshima M, Okano K, Muraki S, et al. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258:336–46.

    Article  PubMed  Google Scholar 

  86. Liu F, Korc M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012;11:2138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Heilmann AM, Perera RM, Ecker V, et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 2014;74:3947–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5:6512–25.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Franco J, Balaji U, Freinkman E, et al. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 2016;14:979–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Finn RS, Crown JP, Ettl J, et al. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res. 2016;18:67.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48.

    Article  CAS  PubMed  Google Scholar 

  92. Infante JR, Cassier PA, Gerecitano JF, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016;22(23):5696–705.

    Article  CAS  PubMed  Google Scholar 

  93. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30.

    Article  PubMed  CAS  Google Scholar 

  94. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cox AD, Fesik SW, Kimmelman AC, et al. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lemoine NR, Jain S, Hughes CM, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology. 1992;102:230–6.

    Article  CAS  PubMed  Google Scholar 

  98. Feldmann G, Beaty R, Hruban RH, Maitra A. Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg. 2007;14:224–32.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142(730–733):e9.

    Google Scholar 

  100. Kopp JL, von Figura G, Mayes E, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:737–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122:639–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Daniluk J, Liu Y, Deng D, et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest. 2012;122:1519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Huang H, Daniluk J, Liu Y, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene. 2014;33:532–5.

    Article  CAS  PubMed  Google Scholar 

  104. Logsdon CD, Lu W. The significance of Ras activity in pancreatic cancer initiation. Int J Biol Sci. 2016;12:338–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149:656–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Collins MA, Brisset J-C, Zhang Y, et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PloS One. 2012;7:e49707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Singh A, Greninger P, Rhodes D, et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15:489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144:1220–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Macdonald JS, McCoy S, Whitehead RP, et al. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest Oncology Group (SWOG 9924) study. Invest New Drugs. 2005;23:485–7.

    Article  CAS  PubMed  Google Scholar 

  110. Ledford H. Cancer: the Ras renaissance. Nature. 2015;520:278–80.

    Article  CAS  PubMed  Google Scholar 

  111. Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kapoor A, Yao W, Ying H, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014;158:185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Viale A, Pettazzoni P, Lyssiotis CA, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514:628–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137:835–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462:108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Corcoran RB, Cheng KA, Hata AN, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 2013;23:121–8.

    Article  CAS  PubMed  Google Scholar 

  117. Steckel M, Molina-Arcas M, Weigelt B, et al. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 2012;22:1227–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kumar MS, Hancock DC, Molina-Arcas M, et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell. 2012;149:642–55.

    Article  CAS  PubMed  Google Scholar 

  119. Bodoky G, Timcheva C, Spigel DR, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30:1216–23.

    Article  CAS  PubMed  Google Scholar 

  120. Infante JR, Somer BG, Park JO, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 1990;2014(50):2072–81.

    Google Scholar 

  121. Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jokinen E, Koivunen JP. MEK and PI3K inhibition in solid tumors: rationale and evidence to date. Ther Adv Med Oncol. 2015;7:170–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Alagesan B, Contino G, Guimaraes AR, et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin Cancer Res. 2015;21:396–404.

    Article  CAS  PubMed  Google Scholar 

  124. Tolcher AW, Bendell JC, Papadopoulos KP, et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann Oncol. 2015;26:58–64.

    Article  CAS  PubMed  Google Scholar 

  125. Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21:730–8.

    Article  CAS  PubMed  Google Scholar 

  126. Ko AH, Bekaii-Saab T, Van Ziffle J, et al. A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res. 2016;22:61–8.

    Article  CAS  PubMed  Google Scholar 

  127. Strong JE, Coffey MC, Tang D, et al. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 1998;17:3351–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mahalingam, D. Oncolytic virus therapy in pancreatic cancer: clinical efficacy and pharmacodynamic analysis of Reolysin® in combination with gemcitabine in patients with advanced pancreatic adenocarcinoma. Available from: http://www.oncolyticsbiotech.com/wp-content/uploads/2015/07/panc-poster-June22-2015.pdf. Accessed 13 May 2017.

  129. Korc M, Chandrasekar B, Yamanaka Y, et al. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest. 1992;90:1352–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106:1033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hakam A, Fang Q, Karl R, Coppola D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci. 2003;48:1972–8.

    Article  CAS  PubMed  Google Scholar 

  132. Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol. 2003;34:803–8.

    Article  CAS  PubMed  Google Scholar 

  133. Bergmann U, Funatomi H, Yokoyama M, et al. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res. 1995;55:2007–11.

    CAS  PubMed  Google Scholar 

  134. Ebert M, Yokoyama M, Friess H, et al. Induction of platelet-derived growth factor A and B chains and over-expression of their receptors in human pancreatic cancer. Int J Cancer. 1995;62:529–35.

    Article  CAS  PubMed  Google Scholar 

  135. Yamanaka Y, Friess H, Buchler M, et al. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 1993;53:5289–96.

    CAS  PubMed  Google Scholar 

  136. Siddiqi I, Funatomi H, Kobrin MS, et al. Increased expression of keratinocyte growth factor in human pancreatic cancer. Biochem Biophys Res Commun. 1995;215:309–15.

    Article  CAS  PubMed  Google Scholar 

  137. Kornmann M, Ishiwata T, Beger HG, Korc M. Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: evidence for autocrine and paracrine actions. Oncogene. 1997;15:1417–24.

    Article  CAS  PubMed  Google Scholar 

  138. Yu J, Ohuchida K, Mizumoto K, et al. Overexpression of c-met in the early stage of pancreatic carcinogenesis; altered expression is not sufficient for progression from chronic pancreatitis to pancreatic cancer. World J Gastroenterol. 2006;12:3878–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhu G-H, Huang C, Qiu Z-J, et al. Expression and prognostic significance of CD151, c-Met, and integrin alpha3/alpha6 in pancreatic ductal adenocarcinoma. Dig Dis Sci. 2011;56:1090–8.

    Article  CAS  PubMed  Google Scholar 

  140. Neuzillet C, Couvelard A, Tijeras-Raballand A, et al. High c-Met expression in stage I–II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis. Histopathology. 2015;67:664–76.

    Article  PubMed  Google Scholar 

  141. Fujimoto K, Hosotani R, Wada M, et al. Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis. Eur J Cancer. 1990;1998(34):1439–47.

    Google Scholar 

  142. Tang RF, Itakura J, Aikawa T, et al. Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas. 2001;22:285–92.

    Article  CAS  PubMed  Google Scholar 

  143. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer. 2003;2:8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Korc M. Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am. 1998;7:25–41.

    CAS  PubMed  Google Scholar 

  145. Pettazzoni P, Viale A, Shah P, et al. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res. 2015;75:1091–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sun C, Hobor S, Bertotti A, et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 2014;7:86–93.

    Article  CAS  PubMed  Google Scholar 

  147. Manchado E, Weissmueller S, Morris JP, et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 2016;534:647–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Huang GS, Brouwer-Visser J, Ramirez MJ, et al. Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res. 2010;16:2999–3010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fitzgerald JB, Johnson BW, Baum J, et al. MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther. 2014;13:410–25.

    Article  CAS  PubMed  Google Scholar 

  150. Allan DGP. Nimotuzumab: evidence of clinical benefit without rash. Oncologist. 2005;10:760–1.

    Article  PubMed  Google Scholar 

  151. Strumberg D, Schultheis B, Ebert MP, et al. Phase II, randomized, double-blind placebo-controlled trial of nimotuzumab plus gemcitabine compared with gemcitabine alone in patients (pts) with advanced pancreatic cancer (PC). Available from: http://meetinglibrary.asco.org/content/117105-132. Accessed 28 Nov 2016.

  152. Kimura K, Sawada T, Komatsu M, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res. 2006;12:4925–32.

    Article  CAS  PubMed  Google Scholar 

  153. Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 2004;22:706–12.

    Article  CAS  PubMed  Google Scholar 

  154. Ma WW, Fetterly G, LeVea C, et al. 2315 A phase Ib study of the FGFR/VEGFR inhibitor dovitinib (D) combined with gemcitabine (G) and capecitabine (C) in advanced pancreatic cancer patients. Eur J Cancer. 2015;51:S438.

    Article  Google Scholar 

  155. Zhen DB, Griffith KA, Ruch JM, et al. A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. Invest New Drugs. 2016;34:733–9.

    Article  CAS  PubMed  Google Scholar 

  156. Pant S, Saleh M, Bendell J, et al. A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann Oncol. 2014;25:1416–21.

    Article  CAS  PubMed  Google Scholar 

  157. Kindler HL, Wroblewski K, Wallace JA, et al. Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs. 2012;30:382–6.

    Article  CAS  PubMed  Google Scholar 

  158. Bergmann L, Maute L, Heil G, et al. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Eur J Cancer. 1990;2015(51):27–36.

    Google Scholar 

  159. Assenat E, Azria D, Mollevi C, et al. Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the “THERAPY” phase 1-2 trial. Oncotarget. 2015;6:12796–808.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Wu Z, Gabrielson A, Hwang JJ, et al. Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2015;76:1309–14.

    Article  CAS  PubMed  Google Scholar 

  161. Isakoff SJ, Saleh MN, Lugovskoy A, et al. First-in-human study of MM-141: a novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3. Available from: http://meetinglibrary.asco.org/content/140542-158. Accessed 28 Nov 2016.

  162. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10:683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore). 2016;95:S8–19.

    Article  CAS  Google Scholar 

  164. Huang T, Kang W, Cheng ASL, et al. The emerging role of Slit-Robo pathway in gastric and other gastro intestinal cancers. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682238/. Accessed 29 Nov 2016.

  165. Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sancho P, Alcala S, Usachov V, et al. The ever-changing landscape of pancreatic cancer stem cells. Pancreatology. 2016;16:489–96.

    Article  PubMed  Google Scholar 

  167. Raj D, Aicher A, Heeschen C. Concise review: stem cells in pancreatic cancer: from concept to translation. Stem Cells. 2015;33:2893–902.

    Article  PubMed  Google Scholar 

  168. Mazur PK, Einwächter H, Lee M, et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 2010;107:13438–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Thomas MM, Zhang Y, Mathew E, et al. Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis. BMC Cancer. 2014;14:862.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Plentz R, Park J-S, Rhim AD, et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology. 2009;136(1741–9):e6.

    Google Scholar 

  171. Cook N, Frese KK, Bapiro TE, et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med. 2012;209:437–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Cook N, Basu B, Smith D-M, et al. A phase I trial of the γ-secretase inhibitor (GSI) MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma (PDAC). Available from: http://meetinglibrary.asco.org/content/126090-144. Accessed 28 Nov 2016.

  173. Richter S, Bedard PL, Chen EX, et al. A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). Invest New Drugs. 2014;32:243–9.

    Article  CAS  PubMed  Google Scholar 

  174. De Jesus-Acosta A, Laheru D, Maitra A, et al. A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Invest New Drugs. 2014;32:739–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192–205.

    Article  CAS  PubMed  Google Scholar 

  177. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  PubMed  Google Scholar 

  178. Liu J, Pan S, Hsieh MH, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA. 2013;110:20224–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Weekes C, Berlin J, Lenz H-J, et al. Phase 1b study of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (PC). Ann Oncol. 2016;27:367PD.

    Article  Google Scholar 

  180. Gara RK, Kumari S, Ganju A, et al. Slit/Robo pathway: a promising therapeutic target for cancer. Drug Discov Today. 2015;20:156–64.

    Article  CAS  PubMed  Google Scholar 

  181. Hessmann E, Schneider G, Ellenrieder V, Siveke JT. MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. Oncogene. 2016;35:1609–18.

    Article  CAS  PubMed  Google Scholar 

  182. Erkan M, Reiser-Erkan C, Michalski CW, et al. The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. Curr Mol Med. 2012;12:288–303.

    Article  CAS  PubMed  Google Scholar 

  183. Erkan M, Michalski CW, Rieder S, et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2008;6:1155–61.

    Article  PubMed  Google Scholar 

  184. Erkan M, Hausmann S, Michalski CW, et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012;9:454–67.

    Article  CAS  PubMed  Google Scholar 

  185. Wörmann SM, Diakopoulos KN, Lesina M, Algül H. The immune network in pancreatic cancer development and progression. Oncogene. 2014;33:2956–67.

    Article  PubMed  CAS  Google Scholar 

  186. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Catenacci DVT, Junttila MR, Karrison T, et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015;33:4284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.

    Article  CAS  PubMed  Google Scholar 

  191. Hingorani SR, Harris WP, Beck JT, et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22:2848–54.

    Article  CAS  PubMed  Google Scholar 

  192. Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology. 2013;144:1210–9.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Erkan M, Adler G, Apte MV, et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut. 2012;61:172–8.

    Article  CAS  PubMed  Google Scholar 

  194. Riopel MM, Li J, Liu S, et al. β1 integrin-extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function. Lab Invest. 2013;93:31–40.

    Article  CAS  PubMed  Google Scholar 

  195. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32.

    Article  CAS  PubMed  Google Scholar 

  197. Chronopoulos A, Robinson B, Sarper M, et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat Commun. 2016;7:12630.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Oettle H, Seufferlein T, Luger T, et al. Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. Available from: http://meetinglibrary.asco.org/content/92903-114. Accessed 21 Nov 2016.

  200. Whatcott CJ, Hanl H, Von Hoff DD. Orchestrating the tumor microenvironment to improve survival for patients with pancreatic cancer normalization, not destruction. Cancer J. 2015;21:299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Melisi D, Garcia-Carbonero R, Macarulla T, et al. A phase II, double-blind study of galunisertib+gemcitabine (GG) vs gemcitabine+placebo (GP) in patients (pts) with unresectable pancreatic cancer (PC). Available from: http://meetinglibrary.asco.org/content/164929-176. Accessed 21 Nov 2016.

  202. Seidel HM, Lamb P, Rosen J. Pharmaceutical intervention in the JAK/STAT signaling pathway. Oncogene. 2000;19:2645–56.

    Article  CAS  PubMed  Google Scholar 

  203. Fukuda A, Wang SC, Morris JP, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011;19:441–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19:456–69.

    Article  CAS  PubMed  Google Scholar 

  205. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Wörmann SM, Song L, Ai J, et al. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology. 2016;151(180–193):e12.

    Google Scholar 

  207. Laklai H, Miroshnikova YA, Pickup MW, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med. 2016;22:497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Nagathihalli NS, Castellanos JA, Shi C, et al. Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology. 2015;149(1932–43):e9.

    Google Scholar 

  209. Hurwitz HI, Uppal N, Wagner SA, et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol. 2015;33:4039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Vonderheide RH, Bajor DL, Winograd R, et al. CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother. 2013;62:949–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19:6286–95.

    Article  CAS  PubMed  Google Scholar 

  213. Gunderson AJ, Kaneda MM, Tsujikawa T, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6:270–85.

    Article  CAS  PubMed  Google Scholar 

  214. Witkiewicz A, Williams TK, Cozzitorto J, et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg. 2008;206:849–54 (discussion 854–6).

    Article  PubMed  Google Scholar 

  215. Koblish HK, Hansbury MJ, Bowman KJ, et al. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. 2010;9:489–98.

    Article  CAS  PubMed  Google Scholar 

  216. Stromnes IM, Brockenbrough JS, Izeradjene K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. 2014;63:1769–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Steele CW, Karim SA, Leach JDG, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29:832–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Chao T, Furth EE, Vonderheide RH. CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma. Cancer Immunol Res. 2016;4:968–82.

    Article  PubMed  Google Scholar 

  219. Daley D, Zambirinis CP, Seifert L, et al. γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation. Cell. 2016;166(1485–1499):e15.

    Google Scholar 

  220. Okazaki T, Chikuma S, Iwai Y, et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212–8.

    Article  CAS  PubMed  Google Scholar 

  221. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

    Article  PubMed  CAS  Google Scholar 

  223. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  PubMed  Google Scholar 

  225. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

    Article  CAS  PubMed  Google Scholar 

  226. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.

    Article  CAS  PubMed  Google Scholar 

  227. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Humphris JL, Patch A-M, Nones K, et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152(1):68–74.e2.

  229. Nakata B, Wang YQ, Yashiro M, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002;8:2536–40.

    CAS  PubMed  Google Scholar 

  230. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.

    Article  CAS  PubMed  Google Scholar 

  231. Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51.

    Article  CAS  PubMed  Google Scholar 

  232. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  235. Kalyan A, Kircher SM, Mohindra NA, et al. Ipilimumab and gemcitabine for advanced pancreas cancer: a phase Ib study. Available from: http://meetinglibrary.asco.org/content/170974-176. 6 Dec 2016.

  236. Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Holmgaard RB, Zamarin D, Lesokhin A, et al. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine. 2016;6:50–8.

    Article  PubMed  PubMed Central  Google Scholar 

  239. Borazanci EH, Hong DS, Gutierrez M, et al. Ibrutinib + durvalumab (MEDI4736) in patients (pts) with relapsed or refractory (R/R) pancreatic adenocarcinoma (PAC): a phase Ib/II multicenter study. Available from: http://meetinglibrary.asco.org/content/160089-173. Accessed 6 Dec 2016.

  240. De Henau O, Rausch M, Winkler D, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539:443–7.

    Article  PubMed  CAS  Google Scholar 

  241. Kaneda MM, Messer KS, Ralainirina N, et al. PI3Kγ is a molecular switch that controls immune suppression. Nature. 2016;539:437–42.

    Article  CAS  PubMed  Google Scholar 

  242. Zisuh AV, Han T-Q, Zhan S-D. Expression of telomerase & its significance in the diagnosis of pancreatic cancer. Indian J Med Res. 2012;135:26–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Stromnes IM, Schmitt TM, Hulbert A, et al. T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell. 2015;28:638–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Hutcheson J, Balaji U, Porembka MR, et al. Immunologic and metabolic features of pancreatic ductal adenocarcinoma define prognostic subtypes of disease. Clin Cancer Res. 2016;22:3606–17.

    Article  CAS  PubMed  Google Scholar 

  247. Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Guo JY, Teng X, Laddha SV, et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 2016;30:1704–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013;504:296–300.

    Article  CAS  PubMed  Google Scholar 

  250. Yang A, Rajeshkumar NV, Wang X, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 2014;4:905–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Lim JP, Gleeson PA. Macropinocytosis: an endocytic pathway for internalising large gulps. Immunol Cell Biol. 2011;89:836–43.

    Article  CAS  PubMed  Google Scholar 

  252. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602–13.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Li D, Yeung S-CJ, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–8.

    Article  PubMed  PubMed Central  Google Scholar 

  254. Kisfalvi K, Moro A, Sinnett-Smith J, et al. Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas. 2013;42:781–5.

    Article  CAS  PubMed  Google Scholar 

  255. Baur JA, Birnbaum MJ. Control of gluconeogenesis by metformin: does redox trump energy charge? Cell Metab. 2014;20:197–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Cheng G, Zielonka J, Ouari O, et al. Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res. 2016;76:3904–15.

    Article  CAS  PubMed  Google Scholar 

  257. Lonardo E, Cioffi M, Sancho P, et al. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PloS One. 2013;8:e76518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Chaiteerakij R, Petersen GM, Bamlet WR, et al. Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J Clin Oncol. 2016;34:1898–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Kordes S, Pollak MN, Zwinderman AH, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16:839–47.

    Article  CAS  PubMed  Google Scholar 

  260. Kottakis F, Nicolay BN, Roumane A, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016;539:390–5.

    Article  CAS  PubMed  Google Scholar 

  261. Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. World J Gastroenterol. 2014;20:7830–48.

    Article  PubMed  PubMed Central  Google Scholar 

  262. Helming KC, Wang X, Roberts CWM. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell. 2014;26:309–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54:728–36.

    Article  CAS  PubMed  Google Scholar 

  264. Morris KV, Chan SW-L, Jacobsen SE, Looney DJ. Small interfering RNA-induced transcriptional gene silencing in human cells. Science. 2004;305:1289–92.

    Article  CAS  PubMed  Google Scholar 

  265. Li L-C, Okino ST, Zhao H, et al. Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci USA. 2006;103:17337–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Mann KM, Ward JM, Yew CCK, et al. Sleeping beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci USA. 2012;109:5934–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. von Figura G, Fukuda A, Roy N, et al. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat Cell Biol. 2014;16:255–67.

    Article  CAS  Google Scholar 

  268. Xiao Q, Zhou D, Rucki AA, et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res. 2016;76:5395–404.

    Article  CAS  PubMed  Google Scholar 

  269. Shakya R, Gonda T, Quante M, et al. Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. Cancer Res. 2013;73:885–96.

    Article  CAS  PubMed  Google Scholar 

  270. Saleh MH, Wang L, Goldberg MS. Improving cancer immunotherapy with DNA methyltransferase inhibitors. Cancer Immunol Immunother. 2016;65:787–96.

    Article  CAS  PubMed  Google Scholar 

  271. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13:673–91.

    Article  CAS  PubMed  Google Scholar 

  272. Köenig A, Linhart T, Schlengemann K, et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology. 2010;138(1189–1199):e1–2.

    Google Scholar 

  273. Mees ST, Mardin WA, Wendel C, et al. EP300: a miRNA-regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas. Int J Cancer. 2010;126:114–24.

    Article  CAS  PubMed  Google Scholar 

  274. Balasubramanyam K, Varier RA, Altaf M, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004;279:51163–71.

    Article  CAS  PubMed  Google Scholar 

  275. Li M, Zhang Z, Hill DL, et al. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res. 2007;67:1988–96.

    Article  CAS  PubMed  Google Scholar 

  276. Sahu RP, Batra S, Srivastava SK. Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells. Br J Cancer. 2009;100:1425–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Kunnumakkara AB, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67:3853–61.

    Article  CAS  PubMed  Google Scholar 

  278. Wang S-H, Lin P-Y, Chiu Y-C, et al. Curcumin-mediated HDAC inhibition suppresses the DNA damage response and contributes to increased DNA damage sensitivity. PloS One. 2015;10:e0134110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  279. Epelbaum R, Schaffer M, Vizel B, et al. Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer. 2010;62:1137–41.

    Article  CAS  PubMed  Google Scholar 

  280. Kanai M, Yoshimura K, Asada M, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol. 2011;68:157–64.

    Article  CAS  PubMed  Google Scholar 

  281. Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–9.

    Article  CAS  PubMed  Google Scholar 

  282. Sato N, Ohta T, Kitagawa H, et al. FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells. Int J Oncol. 2004;24:679–85.

    CAS  PubMed  Google Scholar 

  283. Kumagai T, Wakimoto N, Yin D, et al. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. Int J Cancer. 2007;121:656–65.

    Article  CAS  PubMed  Google Scholar 

  284. Meidhof S, Brabletz S, Lehmann W, et al. ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med. 2015;7:831–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. von Burstin J, Eser S, Paul MC, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009;137(361–71):371–5.

    Google Scholar 

  286. Wang H, Cao Q, Dudek AZ. Phase II study of panobinostat and bortezomib in patients with pancreatic cancer progressing on gemcitabine-based therapy. Anticancer Res. 2012;32:1027–31.

    CAS  PubMed  Google Scholar 

  287. Jones SF, Infante JR, Spigel DR, et al. Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors. Cancer Invest. 2012;30:481–6.

    Article  CAS  PubMed  Google Scholar 

  288. Millward M, Price T, Townsend A, et al. Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs. 2012;30:2303–17.

    Article  CAS  PubMed  Google Scholar 

  289. Richards DA, Boehm KA, Waterhouse DM, et al. Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study. Ann Oncol. 2006;17:1096–102.

    Article  CAS  PubMed  Google Scholar 

  290. Schwartz YB, Pirrotta V. A new world of polycombs: unexpected partnerships and emerging functions. Nat Rev Genet. 2013;14:853–64.

    Article  CAS  PubMed  Google Scholar 

  291. Avan A, Crea F, Paolicchi E, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012;11:1735–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Toll AD, Dasgupta A, Potoczek M, et al. Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma. Hum Pathol. 2010;41:1205–9.

    Article  CAS  PubMed  Google Scholar 

  293. Kim KH, Kim W, Howard TP, et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015;21:1491–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Ougolkov AV, Bilim VN, Billadeau DD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res. 2008;14:6790–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Cao Q, Wang X, Zhao M, et al. The central role of EED in the orchestration of polycomb group complexes. Nat Commun. 2014;5:3127.

    PubMed  PubMed Central  Google Scholar 

  296. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13:337–56.

    Article  CAS  PubMed  Google Scholar 

  297. Mazur PK, Herner A, Mello SS, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21:1163–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Roy N, Malik S, Villanueva KE, et al. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. Genes Dev. 2015;29:658–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Garcia PL, Miller AL, Kreitzburg KM, et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016;35:833–45.

    Article  CAS  PubMed  Google Scholar 

  300. Huang Y, Nahar S, Nakagawa A, et al. Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. Clin Cancer Res. 2016;22:4259–70.

    Article  CAS  PubMed  Google Scholar 

  301. Hessmann E, Johnsen SA, Siveke JT, Ellenrieder V. Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut. 2017;66(1):168–79.

    Article  PubMed  Google Scholar 

  302. Witkiewicz AK, Balaji U, Eslinger C, et al. Integrated patient-derived models delineate individualized therapeutic vulnerabilities of pancreatic cancer. Cell Rep. 2016;16:2017–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Huang L, Holtzinger A, Jagan I, et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat Med. 2015;21:1364–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Domckek, Susan M. RUCAPANC: an open-label phase 2 trial of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious germline or somatic BRCA mutation. Available from: http://clovisoncology.com/files/Rucaparib_SDomchek_Poster_ASCO2016.pdf. Accessed 14 Nov 2016.

  305. Bahary N, Garrido-Laguna I, Cinar P, et al. Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. Available from: http://meetinglibrary.asco.org/content/170916-176. Accessed 6 Dec 2016.

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Dietrich A. Ruess or Hana Algül.

Ethics declarations

Funding

No sources of funding were received for the preparation of this article.

Conflict of interest

Dietrich A. Ruess, Kivanc Görgülü, Sonja M. Wörmann, and Hana Algül declare they have no conflicts of interest directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruess, D.A., Görgülü, K., Wörmann, S.M. et al. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 34, 331–357 (2017). https://doi.org/10.1007/s40266-017-0453-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-017-0453-y

Keywords

Navigation