Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

Nature Reviews Clinical Oncology volume 12, pages 319–334 (2015)Cite this article

Subjects

Key Points

  • Patient survival after resection of pancreatic ductal adenocarcinoma (PDAC) remains poor and more-effective adjuvant treatments are desperately needed; new strategies under investigation include targeting the tumour stroma and cancer stem cell compartment

  • Neoadjuvant therapy might improve the delivery of chemotherapy and radiation, and can enable early treatment of metastatic PDAC

  • The role of chemoradiotherapy in the treatment of locally advanced PDAC is highly controversial; SMAD4 (DPC4) might represent a biomarker that identifies a subset of patients who could benefit from radiation added to systemic chemotherapy

  • Modest success has been achieved with FOLFIRINOX, and with novel cytotoxic agents (nab-paclitaxel and MM-398, for example) in the metastatic setting

  • Immunotherapy (with the GVAX vaccine) has produced promising results in highly selected patients

  • Preclinical data suggest that therapies that remodel the stroma or increase programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression might unveil activity of immune-checkpoint inhibitors

Abstract

Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Novel therapies and targets in pancreatic cancer.

Similar content being viewed by others

References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).

    PubMed  Google Scholar 

  2. Hidalgo, M. Pancreatic cancer. N. Engl. J. Med. 362, 1605–1617 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Oettle, H. et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297, 267–277 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Villarroel, M. C. et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol. Cancer Ther. 10, 3–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kalser, M. H. & Ellenberg, S. S. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch. Surg. 120, 899–903 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Oettle, H. et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310, 1473–1481 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Winter, J. M. et al. 1,423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J. Gastrointest. Surg. 10, 1199–1210 (2006).

    Article  PubMed  Google Scholar 

  17. Butturini, G. et al. Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch. Surg. 143, 75–83 (2008).

    Article  PubMed  Google Scholar 

  18. Esposito, I. et al. Most pancreatic cancer resections are R1 resections. Ann. Surg. Oncol. 15, 1651–1660 (2008).

    Article  PubMed  Google Scholar 

  19. Herman, J. M. et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J. Clin. Oncol. 26, 3503–3510 (2008).

    Article  PubMed  Google Scholar 

  20. Richter, A. et al. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J. Surg. 27, 324–329 (2003).

    Article  PubMed  Google Scholar 

  21. Neoptolemos, J. P. et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200–1210 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Crane, C. H., Ben-Josef, E. & Small, W. Jr. Chemotherapy for pancreatic cancer. N. Engl. J. Med. 350, 2713–2715 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Qian, L. W. et al. Radiation stimulates HGF receptor/c-MET expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells. Int. J. Cancer 104, 542–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. De Bacco, F. et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl Cancer Inst. 103, 645–661 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Neoptolemos, J. P. et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br. J. Cancer 100, 246–250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Neoptolemos, J. P. et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304, 1073–1081 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  28. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  29. Hartwig, W., Werner, J., Jager, D., Debus, J. & Buchler, M. W. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 14, e476–e485 (2013).

    Article  PubMed  Google Scholar 

  30. Ghaferi, A. A., Birkmeyer, J. D. & Dimick, J. B. Variation in hospital mortality associated with inpatient surgery. N. Engl. J. Med. 361, 1368–1375 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Evans, D. B. et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J. Clin. Oncol. 26, 3496–3502 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Varadhachary, G. R. et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J. Clin. Oncol. 26, 3487–3495 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Epelboym, I. et al. Neoadjuvant therapy and vascular resection during pancreaticoduodenectomy: shifting the survival curve for patients with locally advanced pancreatic cancer. World J. Surg. 38, 1184–1195 (2014).

    Article  PubMed  Google Scholar 

  34. Gillen, S., Schuster, T., Meyer Zum Büschenfelde, C., Friess, H. & Kleeff, J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 7, e1000267 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Andriulli, A. et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann. Surg. Oncol. 19, 1644–1662 (2012).

    Article  PubMed  Google Scholar 

  36. Assifi, M. M. et al. Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery 150, 466–473 (2011).

    Article  PubMed  Google Scholar 

  37. Tempero, M. A. et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J. Natl Compr. Canc. Netw. 12, 1083–1093 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Katz, M. H. et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer 118, 5749–5756 (2012).

    Article  PubMed  Google Scholar 

  39. Greenhalf, W. et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J. Natl Cancer Inst. 106, djt347 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Poplin, E. et al. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J. Clin. Oncol. 31, 4453–4461 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Loehrer, P. J. Sr et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J. Clin. Oncol. 29, 4105–4112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chauffert, B. et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–2001 FFCD/SFRO study. Ann. Oncol. 19, 1592–1599 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor–stromal interactions. Cancer Res. 64, 3215–3222 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Hammel, P. et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international phase III LAP 07 study [abstract]. J. Clin. Oncol. 31 (Suppl.), LBA4003 (2013).

    Article  Google Scholar 

  45. Iacobuzio-Donahue, C. A. et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 27, 1806–1813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bidard, F. C. et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann. Oncol. 24, 2057–2061 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Wilentz, R. E. et al. Immunohistochemical labeling for DPC4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am. J. Pathol. 156, 37–43 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nguyen, N. Q., Ruszkiewicz, A., Chang, D., Bambrick, J. & Biankin, A. V. Biomarker assessment from EUS-guided biopsy to predict outcomes and treatment in pancreatic cancer [abstract]. J. Clin. Oncol. 32 (Suppl. 3), a182 (2014).

    Article  Google Scholar 

  49. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  50. Mukherjee, S. et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 14, 317–326 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sultana, A. et al. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J. Clin. Oncol. 25, 2607–2615 (2007).

    Article  PubMed  Google Scholar 

  52. Bramhall, S. R. et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br. J. Cancer 87, 161–167 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Van Cutsem, E. et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22, 1430–1438 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Kindler, H. L. 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. 28, 3617–3622 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Philip, P. A. 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. 28, 3605–3610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Van Cutsem, E. et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J. Clin. Oncol. 27, 2231–2237 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Kindler, H. L. et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 12, 256–262 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Goncalves, A. et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann. Oncol. 23, 2799–2805 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Rougier, P. 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 49, 2633–2642 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Moore, M. 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. 25, 1960–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Ellis, L. M. et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J. Clin. Oncol. 32, 1277–1280 (2014).

    Article  PubMed  Google Scholar 

  62. Wacker, B. 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. 13, 3913–3921 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Van Cutsem, E. et al. Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study. Br. J. Cancer 111, 2067–2075 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Navas, C. et al. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ormanns, S. et al. pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. BMC Cancer 14, 624 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Eberhard, D. A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. da Cunha Santos, G. et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer 116, 5599–5607 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Kim, S. T. et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol. Cancer Ther. 10, 1993–1999 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Gourgou-Bourgade, S. et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J. Clin. Oncol. 31, 23–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Faris, J. E. et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. Oncologist 18, 543–548 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gunturu, K. S. et al. FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity. Med. Oncol. 30, 361 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Heinemann, V., Boeck, S., Hinke, A., Labianca, R. & Louvet, C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8, 82 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Johnson, D. B. et al. Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next-generation sequencing panel. Oncologist 19, 616–622 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Klumpen, H. J. et al. mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome. J. Clin. Oncol. 29, e150–e153 (2011).

    Article  PubMed  Google Scholar 

  76. Harder, J. et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br. J. Cancer 106, 1033–1038 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Safran, H. et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 22, 706–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Chou, A. et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 5, 78 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Abrams, J. et al. National Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network. Am. Soc. Clin. Oncol. Educ. Book 71–76 (2014).

  80. Chang, D. K., Grimmond, S. M. & Evans, T. R. Mining the genome of exceptional responders. Nat. Rev. Cancer 14, 291–292 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Takebe, N., McShane, L. & Conley, B. Exceptional responders—discovering predictive biomarkers. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2015.19 (2015).

  82. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  83. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  84. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  85. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Drummond, D. C. et al. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 66, 3271–3277 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Von Hoff, D. et al. NAPOLI-1: randomized phase 3 study of MM-398 (nal-IRI), with or without 5-fluoruracil and leucovorin versus 5-fluoruracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy [abstract O-0003]. Ann. Oncol. 25, ii105–ii117 (2014).

    Article  Google Scholar 

  88. Zaniboni, A. et al. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother. Pharmacol. 69, 1641–1645 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Yoo, C. 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 101, 1658–1663 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sun, J. D. et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin. Cancer Res. 18, 758–770 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Ryan, D. P. et al. TH-302 plus gemcitabine (G+T) versus gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (PAC) [abstract]. J. Clin. Oncol. 31 (Suppl. 4), a325 (2013).

    Article  Google Scholar 

  92. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  93. 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. 26, 3785–3790 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. O'Reilly, E. et al. Phase IB trial of cisplatin (C), gemcitabine (G) and veliparib (V) in patients with known or potential BRCA or PALB2-mutated pancreas adenocarcinoma (PC) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a4023 (2014).

    Article  Google Scholar 

  95. Zhen, D. B. et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet. Med. http://dx.doi.org/10.1038/gim.2014.153 (2014).

  96. Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-Ras genes. Cell 53, 549–554 (1988).

    Article  CAS  PubMed  Google Scholar 

  97. Chandra, A. et al. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nat. Cell Biol. 14, 148–158 (2012).

    Article  CAS  Google Scholar 

  98. Laheru, D. et al. Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in pancreatic cancer. Invest. New Drugs 30, 2391–2399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Thompson, H. US National Cancer Institute's new Ras project targets an old foe. Nat. Med. 19, 949–950 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zorde Khvalevsky, E. et al. Mutant KRAS is a druggable target for pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20723–20728 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Infante, J. et al. A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas [abstract]. J. Clin. Oncol. 31 (Suppl. 4), a291 (2013).

    Article  Google Scholar 

  104. Van Cutsem, E. et al. Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer [abstract]. J. Clin. Oncol. 33 (Suppl. 3), a344 (2015).

    Article  Google Scholar 

  105. Zimmermann, G. et al. Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638–642 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Rane, S. G. & Reddy, E. P. Janus kinases: components of multiple signaling pathways. Oncogene 19, 5662–5679 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Quintas-Cardama, A. & Verstovsek, S. Molecular pathways: JAK/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res. 19, 1933–1940 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Baxter, E. J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Verstovsek, S. et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 366, 799–807 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kocher, H. M., Mears, L., Lea, N. C., Raj, K. & Mufti, G. J. JAK V617F missense mutation is absent in pancreatic cancer. Gut 56, 1174–1175 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Teague, A. et al. Next-generation sequencing in pancreatic cancer: revealing genomic mutations beyond KRAS [abstract]. J. Clin. Oncol. 32 (Suppl. 3), a2008 (2014).

    Google Scholar 

  112. Lili, L. N., Matyunina, L. V., Walker, L. D., Daneker, G. W. & McDonald, J. F. Evidence for the importance of personalized molecular profiling in pancreatic cancer. Pancreas 43, 198–211 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Corcoran, R. B. et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hurwitz, H. et al. A randomized double-blind phase 2 study of ruxolitinib (RUX) or placebo (PBO) with capecitabine (CAPE) as second-line therapy in patients (pts) with metastatic pancreatic cancer (mPC) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a4000 (2014).

    Article  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  116. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  117. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  118. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  119. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Le, A., Rajeshkumar, N. V., Maitra, A. & Dang, C. V. Conceptual framework for cutting the pancreatic cancer fuel supply. Clin. Cancer Res. 18, 4285–4290 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wolpin, B. M. et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637–638 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  123. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  124. Chini, C. C. et al. Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors. Clin. Cancer Res. 20, 120–130 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Seltzer, M. J. et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 70, 8981–8987 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Garrido-Laguna, I. et al. Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. Br. J. Cancer 103, 649–655 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wolpin, B. M. et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J. Clin. Oncol. 27, 193–198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Garrido-Laguna, I. et al. Tumor engraftment in nude mice and enrichment in stroma-related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin. Cancer Res. 17, 5793–5800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yauch, R. L. et al. A paracrine requirement for Hedgehog signalling in cancer. Nature 455, 406–410 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Ijichi, H. et al. Inhibiting Cxcr2 disrupts tumor–stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. J. Clin. Invest. 121, 4106–4117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Rudin, C. M. et al. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173–1178 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Von Hoff, D. D. et al. Inhibition of the Hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Madden, J. I. Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. Infinity Pharmaceuticals, Inc.[online], (2012).

  136. Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Erkan, M. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161 (2008).

    Article  PubMed  Google Scholar 

  139. Catenacci, D. V. et al. Final analysis of a phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (HH) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): A University of Chicago phase II consortium study [abstract]. J. Clin. Oncol. 31 (Suppl.), a4012 (2013).

    Google Scholar 

  140. De Jesus-Acosta, A. et al. A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA) [abstract]. J. Clin. Oncol. 32 (Suppl. 3), a257 (2014).

    Article  Google Scholar 

  141. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  143. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  144. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Rasheed, Z. A. et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J. Natl Cancer Inst. 102, 340–351 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jimeno, A. et al. A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol. Cancer Ther. 8, 310–314 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rajeshkumar, N. V. et al. A combination of DR5 agonistic monoclonal antibody with gemcitabine targets pancreatic cancer stem cells and results in long-term disease control in human pancreatic cancer model. Mol. Cancer Ther. 9, 2582–2592 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wormann, S. M., Diakopoulos, K. N., Lesina, M. & Algul, H. The immune network in pancreatic cancer development and progression. Oncogene 33, 2956–2967 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Melero, I., Grimaldi, A. M., Perez-Gracia, J. L. & Ascierto, P. A. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin. Cancer Res. 19, 997–1008 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nomi, T. et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 2151–2157 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  154. Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Alvarez, R. et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109, 926–933 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Frese, K. K. et al. Nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2, 260–269 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Beatty, G. L. et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19, 6286–6295 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Laheru, D. et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 14, 1455–1463 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ercolini, A. M. et al. Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response. J. Exp. Med. 201, 1591–1602 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Le, D. T. et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin. Cancer Res. 18, 858–868 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Le, D. T. et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.57.4244 (2015).

  163. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Middleton, G. et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 15, 829–840 (2014).

    Article  CAS  PubMed  Google Scholar 

  165. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Maus, M. V. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  169. Mellor, A. L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 171, 1652–1655 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Godin-Ethier, J., Hanafi, L. A., Piccirillo, C. A. & Lapointe, R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin. Cancer Res. 17, 6985–6991 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Witkiewicz, A. 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. 206, 849–854 (2008).

    Article  PubMed  Google Scholar 

  172. Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  174. RTOG Radiation Therapy Oncology Group. RTOG 1201 Protocol Information [online], (2014).

  175. Berlin, J. D. et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J. Clin. Oncol. 20, 3270–3275 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Oettle, H. et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann. Oncol. 16, 1639–1645 (2005).

    Article  CAS  PubMed  Google Scholar 

  177. Rocha Lima, C. M. 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. 22, 3776–3783 (2004).

    Article  CAS  PubMed  Google Scholar 

  178. Abou-Alfa, G. K. et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin. Oncol. 24, 4441–4447 (2006).

    Article  CAS  PubMed  Google Scholar 

  179. Colucci, G. 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. 28, 1645–1651 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Poplin, E. 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. 27, 3778–3785 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Cunningham, D. et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 27, 5513–5518 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Ueno, H. 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. 31, 1640–1648 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Oettle, H. 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. 32, 2423–2429 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of I.G.-L. is supported by funding from the NIH National Cancer Institute (Grant P30CA042014-23 to the Huntsman Cancer Institute). The authors thank Joan Aaron for her language editing of this article on a voluntary basis and Claire Gartrell of the Huntsman Cancer Institute, Salt Lake City, UT, USA, for editing Figure 1 before submission.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Oncology, and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah School of Medicine, University of Utah, Suite 2100, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA

    Ignacio Garrido-Laguna

  2. Gastrointestinal Cancer Clinical Research Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro 3, 28029, Madrid, Spain

    Manuel Hidalgo

Authors
  1. Ignacio Garrido-Laguna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel Hidalgo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors made substantial contributions to all stages of the preparation of the manuscript for submission.

Corresponding author

Correspondence to Ignacio Garrido-Laguna.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garrido-Laguna, I., Hidalgo, M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 12, 319–334 (2015). https://doi.org/10.1038/nrclinonc.2015.53

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2015.53

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer