New targeted therapies in pancreatic cancer

World Journal of Gastroenterology

Volumn 21, Issue 20, 2015, Pages 6127-6145

  Seicean, Andrada ^a   Petrusel, Livia ^a   Seicean, Radu ^a  

^a IULIU HATIEGANU UNIVERSITY OF MEDICINE AND PHARMACY   (Romania)

Author keywords

Immunotherapy; Pancreas neoplasm; Vaccines

Indexed keywords

ALGENPANTUCEL L; ANGIOGENESIS INHIBITOR; DENDRITIC CELL VACCINE; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; GEMCITABINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR VACCINE; HISTONE DEACETYLASE; HISTONE DEACETYLASE INHIBITOR; K RAS VACCINE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MICRORNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MUCIN 1 VACCINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHOTRANSFERASE; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; RAF PROTEIN; RAS PROTEIN; RECOMBINANT VACCINE; SCATTER FACTOR RECEPTOR; SOMATOMEDIN RECEPTOR; TELOMERASE PEPTIDE VACCINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANTINEOPLASTIC AGENT; CANCER VACCINE; PROTEIN KINASE INHIBITOR; TUMOR MARKER;

ADOPTIVE IMMUNOTHERAPY; CANCER IMMUNOTHERAPY; CANCER PATIENT; CANCER PROGNOSIS; CANCER STEM CELL; CANCER SURVIVAL; CHEMORADIOTHERAPY; DNA REPAIR; EXTRACELLULAR MATRIX; HUMAN; MOLECULARLY TARGETED THERAPY; NONHUMAN; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STROMA CELL; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; ENZYMOLOGY; GENETICS; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; PANCREATIC NEOPLASMS; PATHOLOGY; PERSONALIZED MEDICINE; PROCEDURES; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; CANCER VACCINES; DNA REPAIR; HUMANS; IMMUNOTHERAPY; MOLECULAR TARGETED THERAPY; NEOPLASTIC STEM CELLS; PANCREATIC NEOPLASMS; PRECISION MEDICINE; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84930857148     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v21.i20.6127     Document Type: Review

References (197)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277-300 [PMID: 20610543 DOI: 10.3322/caac.20073]
2. Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg 1999; 189: 1-7 [PMID: 10401733 DOI: 10.1016/S1072-7515(99)00075-7]
3. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Büchler MW. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200-1210 [PMID: 15028824 DOI: 10.1056/NEJMoa032295]
4. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. 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: 2403-2413 [PMID: 9196156]
5. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB. 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 2002; 20: 3270-3275 [PMID: 12149301]
6. Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol 2013; 24: 1972-1979 [PMID: 23670093 DOI: 10.1093/annonc/mdt166]
7. Matsuda K, Idezawa T, You XJ, Kothari NH, Fan H, Korc M. Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. Cancer Res 2002; 62: 5611-5617 [PMID: 12359775]
8. Perugini RA, McDade TP, Vittimberga FJ, Callery MP. Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J Surg Res 2000; 90: 39-44 [PMID: 10781373]
9. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996; 93: 3636-3641 [PMID: 8622988 DOI: 10.1073/pnas.93.8.3636]
10. Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR. AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001; 61: 589-593 [PMID: 11212254]
11. Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012; 22: 304-317 [PMID: 22975374 DOI: 10.1016/j.ccr.2012.07.024]
12. Navas C, Hernández-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 2012; 22: 318-330 [PMID: 22975375]
13. Safran H, Steinhoff M, Mangray S, Rathore R, King TC, Chai L, Berzein K, Moore T, Iannitti D, Reiss P, Pasquariello T, Akerman P, Quirk D, Mass R, Goldstein L, Tantravahi U. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol 2001; 24: 496-499 [PMID: 11586103 DOI: 10.1097/00000421-200110000-00016]
14. Lemoine NR, Hughes CM, Barton CM, Poulsom R, Jeffery RE, Klöppel G, Hall PA, Gullick WJ. The epidermal growth factor receptor in human pancreatic cancer. J Pathol 1992; 166: 7-12 [PMID: 1538276 DOI: 10.1002/path.1711660103]
15. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993; 13: 565-569 [PMID: 8317885]
16. Dong M, Nio Y, Guo KJ, Tamura K, Tian YL, Dong YT. Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. Anticancer Res 1998; 18: 4613-4619 [PMID: 9891528]
17. Tobita K, Kijima H, Dowaki S, Kashiwagi H, Ohtani Y, Oida Y, Yamazaki H, Nakamura M, Ueyama Y, Tanaka M, Inokuchi S, Makuuchi H. Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int J Mol Med 2003; 11: 305-309 [PMID: 12579331]
18. Campoli M, Ferris R, Ferrone S, Wang X. Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies. Clin Cancer Res 2010; 16: 11-20 [PMID: 20028761 DOI: 10.1158/1078-0432.CCR-09-2345]
19. Burtness B, Powell M, Catalano P, Berlin J, Liles DK, Chapman AE, Mitchell E, Benson AB. Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel Plus Cetuximab for Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study. Am J Clin Oncol 2014; Epub ahead of print [PMID: 24685886]
20. Fensterer H, Schade-Brittinger C, Müller HH, Tebbe S, Fass J, Lindig U, Settmacher U, Schmidt WE, Märten A, Ebert MP, Kornmann M, Hofheinz R, Endlicher E, Brendel C, Barth PJ, Bartsch DK, Michl P, Gress TM. Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP). Ann Oncol 2013; 24: 2576-2581 [PMID: 23897705 DOI: 10.1093/annonc/mdt270]
21. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD. 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: 3605-3610 [PMID: 20606093 DOI: 10.1200/JCO.2009.25.7550]
22. Munter M, Timke C, Abdollahi A, Friess H, Jaeger D, Heeger S, Buchler M, Debus J, Huber P, Krempien R. Final results of a phase II trial [PARC-Study ISRCTN56652283] for patients with primary inoperable locally advanced pancreatic cancer combining intensity modulated radiotherapy (IMRT) with cetuximab and gemcitabine. J Clin Oncol 2008; 26 (suppl): 4613
23. Lim JY, Cho JH, Lee SJ, Lee DK, Yoon DS, Cho JY. Gemcitabine Combined with Capecitabine Compared to Gemcitabine with or without Erlotinib as First-Line Chemotherapy in Patients with Advanced Pancreatic Cancer. Cancer Res Treat 2015; 47: 266-273 [PMID: 25327494 DOI: 10.4143/crt.2013.158]
24. Philip PA, Goldman B, Ramanathan RK, Lenz HJ, Lowy AM, Whitehead RP, Wakatsuki T, Iqbal S, Gaur R, Benedetti JK, Blanke CD. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). Cancer 2014; 120: 2980-2985 [PMID: 25041791 DOI: 10.1002/cncr.28744]
25. Watkins DJ, Starling N, Cunningham D, Thomas J, Webb J, Brown G, Barbachano Y, Oates J, Chau I. The combination of a chemotherapy doublet (gemcitabine and capecitabine) with a biological doublet (bevacizumab and erlotinib) in patients with advanced pancreatic adenocarcinoma. The results of a phase I/II study. Eur J Cancer 2014; 50: 1422-1429 [PMID: 24613126 DOI: 10.1016/j.ejca.2014.02.003]
26. Herman JM, Fan KY, Wild AT, Hacker-Prietz A, Wood LD, Blackford AL, Ellsworth S, Zheng L, Le DT, De Jesus-Acosta A, Hidalgo M, Donehower RC, Schulick RD, Edil BH, Choti MA, Hruban RH, Pawlik TM, Cameron JL, Laheru DA, Wolfgang CL. Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2013; 86: 678-685 [PMID: 23773391 DOI: 10.1016/j.ijrobp.2013.03.032]
27. Feliu J, Borrega P, León A, López-Gómez L, López M, Castro J, Belda-Iniesta C, Barriuso J, Martínez V, González-Barón M. Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer. Cancer Chemother Pharmacol 2011; 67: 215-221 [PMID: 20927525 DOI: 10.1007/s00280-010-1472-0]
28. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W. 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: 1960-1966 [PMID: 17452677]
29. Harder J, Ihorst G, Heinemann V, Hofheinz R, Moehler M, Buechler P, Kloeppel G, Röcken C, Bitzer M, Boeck S, Endlicher E, Reinacher-Schick A, Schmoor C, Geissler M. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer 2012; 106: 1033-1038 [PMID: 22374460 DOI: 10.1038/bjc.2012.18]
30. Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C, Hesketh P, Rathore R, Wolff R, Tantravahi U, Hughes TM, Maia C, Pasquariello T, Goldstein L, King T, Tsai JY, Kennedy T. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004; 22: 706-712 [PMID: 15581051 DOI: 10.1081/CNV-200032974]
31. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, Tebbutt NC. 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: 1216-1223 [PMID: 21594619 DOI: 10.1007/s10637-011-9687-4]
32. Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, Oh DY, Liu Y, Redhu S, Steplewski K, Le N. 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 2014; 50: 2072-2081 [PMID: 24915778 DOI: 10.1016/j.ejca.2014.04.024]
33. Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, ͆wieboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol 2015; 26: 921-927 [PMID: 25609246]
34. McCaffery I, Tudor Y, Deng H, Tang R, Suzuki S, Badola S, Kindler HL, Fuchs CS, Loh E, Patterson SD, Chen L, Gansert JL. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res 2013; 19: 4282-4289 [PMID: 23741071 DOI: 10.1158/1078-0432.CCR-12-1840]
35. Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, McGreivy J, Bray SL, Hei Y, Feigal EG, Loh E, Fuchs CS. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol 2012; 23: 2834-2842 [PMID: 22700995 DOI: 10.1093/annonc/mds142]
36. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. 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 2002; 87: 161-167 [PMID: 12107836 DOI: 10.1038/sj.bjc.6600446]
37. De Jesus-Acosta A, Laheru D, Maitra A, Arcaroli J, Rudek MA, Dasari A, Blatchford PJ, Quackenbush K, Messersmith W. A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Invest New Drugs 2014; 32: 739-745 [PMID: 24668033 DOI: 10.1007/s10637-014-0083-8]
38. Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015; 107: [PMID: 25638248 DOI: 10.1093/jnci/dju413]
39. Hosein PJ, de Lima Lopes G, Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol 2013; 36: 151-156 [PMID: 22307213 DOI: 10.1097/COC.0b013e3182436e8c]
40. Sahora K, Schindl M, Kuehrer I, Eisenhut A, Werba G, Brostjan C, Telek B, Ba'ssalamah A, Stift J, Schoppmann SF, Gnant M. A phase II trial of two durations of Bevacizumab added to neoadjuvant gemcitabine for borderline and locally advanced pancreatic cancer. Anticancer Res 2014; 34: 2377-2384 [PMID: 24778046]
41. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM. 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: 3617-3622 [PMID: 20606091 DOI: 10.1200/JCO.2010.28.1386]
42. Crane CH, Winter K, Regine WF, Safran H, Rich TA, Curran W, Wolff RA, Willett CG. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. J Clin Oncol 2009; 27: 4096-4102 [PMID: 19636002 DOI: 10.1200/JCO.2009.21.8529]
43. Ko AH, Venook AP, Bergsland EK, Kelley RK, Korn WM, Dito E, Schillinger B, Scott J, Hwang J, Tempero MA. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol 2010; 66: 1051-1057 [PMID: 20130876 DOI: 10.1007/s00280-010-1257-5]
44. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009; 27: 2231-2237 [PMID: 19307500 DOI: 10.1200/JCO.2008.20.0238]
45. Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial. Jpn J Clin Oncol 2015; 45: 439-448 [PMID: 25647781]
46. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Létourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008; 371: 2101-2108 [PMID: 18514303 DOI: 10.1016/S0140-6736(08)60661-3]
47. Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 2011; 12: 256-262 [PMID: 21306953 DOI: 10.1016/S1470-2045(11)70004-3]
48. Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA. 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 2013; 49: 2633-2642 [PMID: 23642329 DOI: 10.1016/j.ejca.2013.04.002]
49. Chiorean EG, Schneider BP, Akisik FM, Perkins SM, Anderson S, Johnson CS, DeWitt J, Helft P, Clark R, Johnston EL, Spittler AJ, Deluca J, Bu G, Shahda S, Loehrer PJ, Sandrasegaran K, Cardenes HR. Phase 1 pharmacogenetic and pharmacodynamic study of sorafenib with concurrent radiation therapy and gemcitabine in locally advanced unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2014; 89: 284-291 [PMID: 24726286 DOI: 10.1016/j.ijrobp.2014.02.024]
50. Cascinu S, Berardi R, Sobrero A, Bidoli P, Labianca R, Siena S, Ferrari D, Barni S, Aitini E, Zagonel V, Caprioni F, Villa F, Mosconi S, Faloppi L, Tonini G, Boni C, Conte P, Di Costanzo F, Cinquini M. Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study. Dig Liver Dis 2014; 46: 182-186 [PMID: 24189171 DOI: 10.1016/j.dld.2013.09.020]
51. Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. 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 2012; 23: 2799-2805 [PMID: 22771827 DOI: 10.1093/annonc/mds135]
52. Tian W, Ding W, Kim S, Xu X, Pan M, Chen S. Efficacy and safety profile of combining agents against epidermal growth factor receptor or vascular endothelium growth factor receptor with gemcitabine-based chemotherapy in patients with advanced pancreatic cancer: a meta-analysis. Pancreatology 2013; 13: 415-422 [PMID: 23890141 DOI: 10.1016/j.pan.2013.04.195]
53. Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 2013; 19: 1389-1400 [PMID: 24202392 DOI: 10.1038/nm.3388]
54. da Cunha Santos G, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS. 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 2010; 116: 5599-5607 [PMID: 20824720 DOI: 10.1002/cncr.25393]
55. Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, Enzinger PC, Kwak EL, Muzikansky A, Lawrence C, Fuchs CS. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 2007; 25: 4787-4792 [PMID: 17947726 DOI: 10.1200/JCO.2007.11.8521]
56. Renouf DJ, Tang PA, Hedley D, Chen E, Kamel-Reid S, Tsao MS, Tran-Thanh D, Gill S, Dhani N, Au HJ, Wang L, Moore MJ. A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. Eur J Cancer 2014; 50: 1909-1915 [PMID: 24857345 DOI: 10.1016/j.ejca.2014.04.008]
57. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Vehling-Kaiser U, Winkelmann C, Fischer von Weikersthal L, Clemens MR, Gauler TC, Märten A, Klein S, Kojouharoff G, Barner M, Geissler M, Greten TF, Mansmann U, Kirchner T, Heinemann V. 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: 469-476 [PMID: 23169292 DOI: 10.1038/bjc.2012.495]
58. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, Heinemann V. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol 2013; 48: 544-548 [PMID: 23435671 DOI: 10.1007/s00535-013-0767-4]
59. Brell JM, Matin K, Evans T, Volkin RL, Kiefer GJ, Schlesselman JJ, Dranko S, Rath L, Schmotzer A, Lenzner D, Ramanathan RK. Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology 2009; 76: 270-274 [PMID: 19258727 DOI: 10.1159/000206141]
60. Singla S, Pippin JA, Drebin JA. Dual ErbB1 and ErbB2 receptor tyrosine kinase inhibition exerts synergistic effect with conventional chemotherapy in pancreatic cancer. Oncol Rep 2012; 28: 2211-2216 [PMID: 23007710]
61. Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, Burris H, Rosen P, Hidalgo M, Ritch P, Baker AF, Raghunand N, Crowley J, Von Hoff DD. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol 2014; 74: 379-387 [PMID: 24939212 DOI: 10.1007/s00280-014-2499-4]
62. Saxby AJ, Nielsen A, Scarlett CJ, Clarkson A, Morey A, Gill A, Smith RC. Assessment of HER-2 status in pancreatic adenocarcinoma: correlation of immunohistochemistry, quantitative real-time RT-PCR, and FISH with aneuploidy and survival. Am J Surg Pathol 2005; 29: 1125-1134 [PMID: 16096400 DOI: 10.1097/01.pas.0000160979.85457.73]
63. Walsh N, Kennedy S, Larkin A, Corkery B, O'Driscoll L, Clynes M, Crown J, O'Donovan N. EGFR and HER2 inhibition in pancreatic cancer. Invest New Drugs 2013; 31: 558-566 [PMID: 23076814 DOI: 10.1007/s10637-012-9891-x]
64. Maron R, Schechter B, Mancini M, Mahlknecht G, Yarden Y, Sela M. Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc Natl Acad Sci USA 2013; 110: 15389-15394 [PMID: 24003140 DOI: 10.1073/pnas.1313857110]
65. Larbouret C, Gaborit N, Chardès T, Coelho M, Campigna E, Bascoul-Mollevi C, Mach JP, Azria D, Robert B, Pèlegrin A. In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' downregulation and dimers' disruption. Neoplasia 2012; 14: 121-130 [PMID: 22431920]
66. Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, Reddy SA, Krishnan K. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 2011; 51: 1164-1174 [PMID: 21723941 DOI: 10.1016/j.freeradbiomed.2011.06.008]
67. Ko AH, Tempero MA, Bekaii-Saab TB, Kuhn P, Courtin R, Ziyeh S, Tahiri S, Kelley RK, Dito E, Ong A, Linetskaya R, Mirzoeva OK, Wu C, Venook AP, Korn WM. Dual mek/egfr inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (azd6244; arry-142886) plus erlotinib. J Clin Oncol 2013; 31(suppl): 4014a
68. Hirakawa T, Yashiro M, Murata A, Hirata K, Kimura K, Amano R, Yamada N, Nakata B, Hirakawa K. IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer. BMC Cancer 2013; 13: 392 [PMID: 23962053 DOI: 10.1186/1471-2407-13-392]
69. Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H. Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells. BMC Cancer 2013; 13: 41 [PMID: 23367880 DOI: 10.1186/1471-2407-13-41]
70. Avan A, Caretti V, Funel N, Galvani E, Maftouh M, Honeywell RJ, Lagerweij T, Van Tellingen O, Campani D, Fuchs D, Verheul HM, Schuurhuis GJ, Boggi U, Peters GJ, Würdinger T, Giovannetti E. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. Cancer Res 2013; 73: 6745-6756 [PMID: 24085787 DOI: 10.1158/0008-5472.CAN-13-0837]
71. Avan A, Quint K, Nicolini F, Funel N, Frampton AE, Maftouh M, Pelliccioni S, Schuurhuis GJ, Peters GJ, Giovannetti E. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des 2013; 19: 940-950 [PMID: 22973962 DOI: 10.2174/1381612811306050940]
72. Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, Pasca di Magliano M, Simeone DM. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011; 141: 2218-2227.e5 [PMID: 21864475 DOI: 10.1053/j.gastro.2011.08.009]
73. Hage C, Rausch V, Giese N, Giese T, Schönsiegel F, Labsch S, Nwaeburu C, Mattern J, Gladkich J, Herr I. The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Cell Death Dis 2013; 4: e627 [PMID: 23661005 DOI: 10.1038/cddis.2013.158]
74. Ucar DA, Magis AT, He DH, Lawrence NJ, Sebti SM, Kurenova E, Zajac-Kaye M, Zhang J, Hochwald SN. Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo. Anticancer Agents Med Chem 2013; 13: 595-602 [PMID: 23272972 DOI: 10.2174/1871520611313040009]
75. Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, Enzinger PC, Allen B, Clark JW, Ryan DP, Fuchs CS. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol 2009; 27: 193-198 [PMID: 19047305 DOI: 10.1200/JCO.2008.18.9514]
76. Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, Davis D, Zhang Y, Wolff RA, Abbruzzese JL. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer 2010; 10: 368 [PMID: 20630061 DOI: 10.1186/1471-2407-10-368]
77. Richards DA, Kuefler PR, Becerra C, Wilfong LS, Gersh RH, Boehm KA, Zhan F, Asmar L, Myrand SP, Hozak RR, Zhao L, Gill JF, Mullaney BP, Obasaju CK, Nicol SJ. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Invest New Drugs 2011; 29: 144-153 [PMID: 19714296 DOI: 10.1007/s10637-009-9307-8]
78. Onconova Therapeutics. Onconova Announces Results of Interim Analysis of Metastatic Pancreatic Cancer Study, 2013. Available from: URL: http://investor.onconova.com/releasedetail.cfm? ReleaseID5814465. Accessed July 14, 2014
79. Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med 2009; 133: 365-374 [PMID: 19260742]
80. Jacob DA, Bahra M, Langrehr JM, Boas-Knoop S, Stefaniak R, Davis J, Schumacher G, Lippert S, Neumann UP. Combination therapy of poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide and gemcitabine shows strong antitumor activity in pancreatic cancer cells. J Gastroenterol Hepatol 2007; 22: 738-748 [PMID: 17444865]
81. Fogelman DR, Wolff RA, Kopetz S, Javle M, Bradley C, Mok I, Cabanillas F, Abbruzzese JL. Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer. Anticancer Res 2011; 31: 1417-1420 [PMID: 21508395]
82. Pishvaian MJ, Slack R, Witkiewicz A, He AR He, Hwang JJ, Hankin A, Ley L, Apte SK, Littman SJ, Weiner LM, Marshall J, Brody JR. A phase I/II study of the PARP inhibitor, ABT-888 plus 5-fluorouracil and oxaliplatin (modified FOLFOX-6) in patients with metastatic pancreatic cancer. Proceedings of the ASCO Annual Meeting, 2011
83. Lee JK, Ryu JK, Yang KY, Woo SM, Park JK, Yoon WJ, Lee SH, Jeong KS, Kim YT, Yoon YB. Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer. Pancreas 2011; 40: 966-973 [PMID: 21487323 DOI: 10.1097/MPA.0b013e3182156d5a]
84. Deorukhkar A, Shentu S, Park HC, Diagaradjane P, Puduvalli V, Aggarwal B, Guha S, Krishnan S. Inhibition of radiationinduced DNA repair and prosurvival pathways contributes to vorinostat-mediated radiosensitization of pancreatic cancer cells. Pancreas 2010; 39: 1277-1283 [PMID: 20531243 DOI: 10.1097/MPA.0b013e3181dd63e1]
85. Arnold NB, Arkus N, Gunn J, Korc M. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances gemcitabine-induced cell death in pancreatic cancer. Clin Cancer Res 2007; 13: 18-26 [PMID: 17200334 DOI: 10.1158/1078-0432.CCR-06-0914]
86. Sung V, Richard N, Brady H, Maier A, Kelter G, Heise C. Histone deacetylase inhibitor MGCD0103 synergizes with gemcitabine in human pancreatic cells. Cancer Sci 2011; 102: 1201-1207 [PMID: 21375679 DOI: 10.1111/j.1349-7006.2011.01921.x]
87. Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, Mathe EA, Jen J, Yang P, Sugimura H, Gemma A, Kudoh S, Croce CM, Harris CC. MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci USA 2009; 106: 12085-12090 [PMID: 19597153 DOI: 10.1073/pnas.0905234106]
88. Dillhoff M, Liu J, Frankel W, Croce C, Bloomston M. MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg 2008; 12: 2171-2176 [PMID: 18642050 DOI: 10.1007/s11605-008-0584-x]
89. Ali S, Almhanna K, Chen W, Philip PA, Sarkar FH. Differentially expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. Am J Transl Res 2010; 3: 28-47 [PMID: 21139804]
90. Schultz NA, Andersen KK, Roslind A, Willenbrock H, Wøjdemann M, Johansen JS. Prognostic microRNAs in cancer tissue from patients operated for pancreatic cancer - five microRNAs in a prognostic index. World J Surg 2012; 36: 2699-2707 [PMID: 22851141 DOI: 10.1007/s00268-012-1705-y]
91. Hwang JH, Voortman J, Giovannetti E, Steinberg SM, Leon LG, Kim YT, Funel N, Park JK, Kim MA, Kang GH, Kim SW, Del Chiaro M, Peters GJ, Giaccone G. Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 2010; 5: e10630 [PMID: 20498843 DOI: 10.1371/journal.pone.0010630]
92. Dong J, Zhao YP, Zhou L, Zhang TP, Chen G. Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch Med Res 2011; 42: 8-14 [PMID: 21376256 DOI: 10.1016/j.arcmed.2011.01.006]
93. Sarkar S, Dubaybo H, Ali S, Goncalves P, Kollepara SL, Sethi S, Philip PA, Li Y. Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am J Cancer Res 2013; 3: 465-477 [PMID: 24224124]
94. Park JK, Lee EJ, Esau C, Schmittgen TD. Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma. Pancreas 2009; 38: e190-e199 [PMID: 19730150 DOI: 10.1097/MPA.0b013e3181ba82e1]
95. Cai B, An Y, Lv N, Chen J, Tu M, Sun J, Wu P, Wei J, Jiang K, Miao Y. miRNA-181b increases the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine in vitro and in nude mice by targeting BCL-2. Oncol Rep 2013; 29: 1769-1776 [PMID: 23440261]
96. Yan H, Wu J, Liu W, Zuo Y, Chen S, Zhang S, Zeng M, Huang W. MicroRNA-20a overexpression inhibited proliferation and metastasis of pancreatic carcinoma cells. Hum Gene Ther 2010; 21: 1723-1734 [PMID: 20583868 DOI: 10.1089/hum.2010.061]
97. Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, Liu J, Yu J, Chen J. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res 2010; 70: 6015-6025 [PMID: 20610624 DOI: 10.1158/0008-5472.CAN-09-4531]
98. Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS, Xu L. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4: e6816 [PMID: 19714243 DOI: 10.1371/journal.pone.0006816]
99. Moriyama T, Ohuchida K, Mizumoto K, Yu J, Sato N, Nabae T, Takahata S, Toma H, Nagai E, Tanaka M. MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol Cancer Ther 2009; 8: 1067-1074 [PMID: 19435867 DOI: 10.1158/1535-7163.MCT-08-0592]
100. Habbe N, Koorstra JB, Mendell JT, Offerhaus GJ, Ryu JK, Feldmann G, Mullendore ME, Goggins MG, Hong SM, Maitra A. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 2009; 8: 340-346 [PMID: 19106647 DOI: 10.4161/cbt.8.4.7338]
101. Chen C, Zhang Y, Zhang L, Weakley SM, Yao Q. MicroRNA-196: critical roles and clinical applications in development and cancer. J Cell Mol Med 2011; 15: 14-23 [PMID: 21091634 DOI: 10.1111/j.1582-4934.2010.01219.x]
102. Torrisani J, Bournet B, du Rieu MC, Bouisson M, Souque A, Escourrou J, Buscail L, Cordelier P. let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gene Ther 2009; 20: 831-844 [PMID: 19323605 DOI: 10.1089/hum.2008.134]
103. Zhao WG, Yu SN, Lu ZH, Ma YH, Gu YM, Chen J. The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis 2010; 31: 1726-1733 [PMID: 20675343 DOI: 10.1093/carcin/bgq160]
104. Li Y, Vandenboom TG, Wang Z, Kong D, Ali S, Philip PA, Sarkar FH. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res 2010; 70: 1486-1495 [PMID: 20124483 DOI: 10.1158/0008-5472.CAN-09-2792]
105. Hou B, Jian Z, Chen S, Ou Y, Li S, Ou J. [Expression of miR-216a in pancreatic cancer and its clinical significance]. Nan Fang Yi Ke Da Xue Xue Bao 2012; 32: 1628-1631 [PMID: 23174591]
106. Strimpakos AS, Saif MW. Update on phase I studies in advanced pancreatic adenocarcinoma. Hunting in darkness? JOP 2013; 14: 354-358 [PMID: 23846926]
107. Stephenson J, Richards DA, Wolpin BM, Becerra C, Hamm JT, Messersmith WA, Devens S, Cushing J, Goddard J, Schmalbach T, Fuchs CS. The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer. J Clin Oncol 2011; 29 suppl: Abstr 4114
108. Oettle H, Hilbig A, Seufferlein T, Schmid RM, Luger T, von Wichert G, Schmaus S, Heinrichs H, Schlingensiepen K. Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma. J Clin Oncol 2009; 27 suppl: Abstr 4619.
109. Yabuuchi S, Pai SG, Campbell NR, de Wilde RF, De Oliveira E, Korangath P, Streppel MM, Rasheed ZA, Hidalgo M, Maitra A, Rajeshkumar NV. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett 2013; 335: 41-51 [PMID: 23402814 DOI: 10.1016/j.canlet.2013.01.054]
110. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455-2465 [PMID: 22658128 DOI: 10.1056/NEJMoa1200694]
111. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013; 36: 382-389 [PMID: 23924790 DOI: 10.1097/CJI.0b013e31829fb7a2]
112. Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O'Dwyer PJ. 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: 6286-6295 [PMID: 23983255 DOI: 10.1158/1078-0432.CCR-13-1320]
113. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg 2011; 253: 328-335 [PMID: 21217520 DOI: 10.1097/SLA.0b013e3181fd271c]
114. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E. 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 2008; 14: 1455-1463 [PMID: 18316569 DOI: 10.1158/1078-0432.CCR-07-0371]
115. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239-252 [PMID: 19279573 DOI: 10.1038/nrc2618]
116. Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997; 89: 1260-1270 [PMID: 9293916 DOI: 10.1093/jnci/89.17.1260]
117. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003; 21: 3296-3302 [PMID: 12947065 DOI: 10.1200/JCO.2003.02.098]
118. Toole BP, Slomiany MG. Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin Cancer Biol 2008; 18: 244-250 [PMID: 18534864 DOI: 10.1016/j.semcancer.2008.03.009]
119. Hanks BA, Holtzhausen A, Gimpel P, Jamieson R, Campbell OM, Sun L, Augustine CK, Tyler DS, Osada T, Morse M, Ling LE, Lyerly HK, Blobe GC. Effect of the loss of the type III TGF β receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ related biomarkers to enhance immunotherapy efficacy. J Clin Oncol 2012; 30: 10563a
120. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10: 415-424 [PMID: 20495575 DOI: 10.1038/nrc2853]
121. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271: 350-353 [PMID: 8553070 DOI: 10.1126/science.271.5247.350]
122. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-1806 [PMID: 18772397 DOI: 10.1126/science.1164368]
123. Xu Y, An Y, Wang X, Zha W, Li X. Inhibition of the Hedgehog pathway induces autophagy in pancreatic ductal adenocarcinoma cells. Oncol Rep 2014; 31: 707-712 [PMID: 24297612]
124. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851-856 [PMID: 14520413 DOI: 10.1038/nature02009]
125. Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med 2009; 361: 2094-2096 [PMID: 19923581 DOI: 10.1056/NEJMcibr0905857]
126. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457-1461 [PMID: 19460966 DOI: 10.1126/science.1171362]
127. Infinity Pharmaceuticals. Infinity Reports Update From Phase 2 Study of Saridegib Plus Gemcitabine in Patients With Metastatic Pancreatic Cancer, 2012. Available from: URL: http://www.businesswire.com/news/home/20120127005146/en/Infinity-Reports-Update-Phase-2-Study-Saridegib#.U8PymNhOV2s. Accessed April 27, 2014
128. Ren H, Jia L, Zhao T, Zhang H, Chen J, Yang S, Liu J, Yu M, Hao J. Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells. Cancer Lett 2014; 354: 172-180 [PMID: 25130171 DOI: 10.1016/j.canlet.2014.08.001]
129. Zhao X, Gao S, Ren H, Sun W, Zhang H, Sun J, Yang S, Hao J. Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin. Cancer Res 2014; 74: 2455-2464 [PMID: 24599125 DOI: 10.1158/0008-5472.CAN-13-3009]
130. Raykov Z, Grekova SP, Bour G, Lehn JM, Giese NA, Nicolau C, Aprahamian M. Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy. Int J Cancer 2014; 134: 2572-2582 [PMID: 24214898 DOI: 10.1002/ijc.28597]
131. Kasuya K, Tsuchida A, Nagakawa Y, Suzuki M, Abe Y, Itoi T, Serizawa H, Nagao T, Shimazu M, Aoki T. Hypoxia-inducible factor-1α expression and gemcitabine chemotherapy for pancreatic cancer. Oncol Rep 2011; 26: 1399-1406 [PMID: 21922147]
132. Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, Kong D, Sethi S, Aboukameel A, Padhye SB, Sarkar FH. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One 2012; 7: e50165 [PMID: 23272057 DOI: 10.1371/journal.pone.0050165]
133. Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 2009; 16: 633-647 [PMID: 19460341 DOI: 10.1016/j.devcel.2009.03.010]
134. O'Reilly EM, Smith LS, Bendell JC, Strickler JH, Zalupski M, Gluck W, Kapoun A, Yen WC, Xu L, Hill D, Zhou L, Dupont J, Cohn AL. Phase 1b of anticancer stem cell antibody omp-59r5 (antinotch 2/3) in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic cancer. J Clin Oncol 2014; 32 (suppl 3): 220a
135. Gracian AC, Jameson MB, Grande E, Cooray P, Parnis F, Grimison P, Jeffery M, Stagg RJ, Dupont J, Tebbutt NC. A phase 1b study of the anticancer stem cell agent demcizumab and gemcitabine with or without paclitaxel protein bound particles in patients with pancreatic cancer. J Clin Oncol 2014; 32 (suppl 3): 279a
136. Desai N, Trieu V, Damascelli B, Soon-Shiong P. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Transl Oncol 2009; 2: 59-64 [PMID: 19412420 DOI: 10.1593/tlo.09109]
137. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29: 4548-4554 [PMID: 21969517 DOI: 10.1200/JCO.2011.36.5742]
138. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, Tuveson DA. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012; 2: 260-269 [PMID: 22585996 DOI: 10.1158/2159-8290.CD-11-0242]
139. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703 [PMID: 24131140 DOI: 10.1056/NEJMoa1304369]
140. Von Hoff DD. Final Results of a Randomized Phase III Study of Weekly Nabpaclitaxel Plus Gemcitabine versus Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas. San Francisco, CA: ASCO, 2013
141. Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, Muñoz M, Quijano Y, Cubillo A, Rodriguez-Pascual J, Plaza C, de Vicente E, Prados S, Tabernero S, Barbacid M, Lopez-Rios F, Hidalgo M. Stromal disrupting effects of nabpaclitaxel in pancreatic cancer. Br J Cancer 2013; 109: 926-933 [PMID: 23907428 DOI: 10.1038/bjc.2013.415]
142. Xie X, Xia W, Li Z, Kuo HP, Liu Y, Li Z, Ding Q, Zhang S, Spohn B, Yang Y, Wei Y, Lang JY, Evans DB, Chiao PJ, Abbruzzese JL, Hung MC. Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models. Cancer Cell 2007; 12: 52-65 [PMID: 17613436 DOI: 10.1016/j.ccr.2007.05.009]
143. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15: 220-231 [PMID: 19249680 DOI: 10.1016/j.ccr.2009.01.027]
144. Kuehn R, Lelkes PI, Bloechle C, Niendorf A, Izbicki JR. Angiogenesis, angiogenic growth factors, and cell adhesion molecules are upregulated in chronic pancreatic diseases: angiogenesis in chronic pancreatitis and in pancreatic cancer. Pancreas 1999; 18: 96-103 [PMID: 9888665 DOI: 10.1097/00006676-199901000-00012]
145. Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000; 88: 2239-2245 [PMID: 10820344 DOI: 10.1002/(SICI)1097-0142(20000515)88]
146. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in latestage pancreatic islet tumors. Cancer Cell 2005; 8: 299-309 [PMID: 16226705 DOI: 10.1016/j.ccr.2005.09.005]
147. Pant S, Martin LK, Geyer S, Wei L, Van Loon K, Sommovilla N, Zalupski M, Iyer R, Fogelman D, Ko AH, Bekaii-Saab T. Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer: A Pooled Analysis of 4 Prospective Trials of Gemcitabine-based Therapy With Bevacizumab. Am J Clin Oncol 2014; Epub ahead of print [PMID: 25068471 DOI: 10.1097/COC.0000000000000108]
148. Taeger J, Moser C, Hellerbrand C, Mycielska ME, Glockzin G, Schlitt HJ, Geissler EK, Stoeltzing O, Lang SA. Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol Cancer Ther 2011; 10: 2157-2167 [PMID: 21885862 DOI: 10.1158/1535-7163.MCT-11-0312]
149. Niccolai E, Prisco D, D'Elios MM, Amedei A. What is recent in pancreatic cancer immunotherapy? Biomed Res Int 2013; 2013: 492372 [PMID: 23509731]
150. Rossi GR, Mautino MR, Unfer RC, Seregina TM, Vahanian N, Link CJ. Effective treatment of preexisting melanoma with whole cell vaccines expressing alpha(1,3)-galactosyl epitopes. Cancer Res 2005; 65: 10555-10561 [PMID: 16288048 DOI: 10.1158/0008-5472.CAN-05-0627]
151. Rossi GR, Unfer RC, Seregina T, Link CJ. Complete protection against melanoma in absence of autoimmune depigmentation after rejection of melanoma cells expressing alpha(1,3)galactosyl epitopes. Cancer Immunol Immunother 2005; 54: 999-1009 [PMID: 15889257]
152. Hardacre J, Mulcahy M, Small W, Talamonti MS, Obel JC, Rocha Lima CMS, Safran H, Lenz HJ, Chiorean EG, Vahanian NN, Link CJ. Addition of algenpantucel-L immunotherapy to standard of care (SOC) adjuvant therapy for pancreatic cancer. J Clin Oncol 2012; 30 Suppl: Abstract 4049
153. Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 2008; 299: 1019-1026 [PMID: 18319412 DOI: 10.1007/s00262-005-0667-4]
154. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539-3543 [PMID: 8097319 DOI: 10.1073/pnas.90.8.3539]
155. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001; 19: 145-156 [PMID: 11134207]
156. De Remigis A, de Gruijl TD, Uram JN, Tzou SC, Iwama S, Talor MV, Armstrong TD, Santegoets SJ, Slovin SF, Zheng L, Laheru DA, Jaffee EM, Gerritsen WR, van den Eertwegh AJ, Le DT, Caturegli P. Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. Int J Cancer 2015; 136: 127-137 [PMID: 24832153 DOI: 10.1002/ijc.28973]
157. Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz RE, Murugesan SR, Leach SD, Jaffee E, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res 2001; 7: 3862-3868 [PMID: 11751476]
158. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 2006; 55: 1294-1298 [PMID: 16315030 DOI: 10.1007/s00262-005-0102-x]
159. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Gedde-Dahl T, Stokke KT, Sølheim BG, Egge TS, Søreide O, Thorsby E, Gaudernack G. Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. Int J Cancer 1996; 65: 450-453 [PMID: 8621226 DOI: 10.1002/(SICI)1097-0215(19960208)65]
160. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E, Gaudernack G. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 1995; 346: 1399-1400 [PMID: 7475823 DOI: 10.1016/S0140-6736(95)92408-6]
161. Carbone DP, Ciernik IF, Kelley MJ, Smith MC, Nadaf S, Kavanaugh D, Maher VE, Stipanov M, Contois D, Johnson BE, Pendleton CD, Seifert B, Carter C, Read EJ, Greenblatt J, Top LE, Kelsey MI, Minna JD, Berzofsky JA. Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome. J Clin Oncol 2005; 23: 5099-5107 [PMID: 15983396 DOI: 10.1200/JCO.2005.03.158]
162. Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Søreide O, Eriksen JA, Møller M, Baksaas I, Lothe RA, Saeterdal I, Gaudernack G. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer 2001; 92: 441-450 [PMID: 11291084 DOI: 10.1002/ijc.1205]
163. Wedén S, Klemp M, Gladhaug IP, Møller M, Eriksen JA, Gaudernack G, Buanes T. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer 2011; 128: 1120-1128 [PMID: 20473937 DOI: 10.1002/ijc.25449]
164. Abou-Alfa GK, Chapman PB, Feilchenfeldt J, Brennan MF, Capanu M, Gansukh B, Jacobs G, Levin A, Neville D, Kelsen DP, O'Reilly EM. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am J Clin Oncol 2011; 34: 321-325 [PMID: 20686403 DOI: 10.1097/COC.0b013e3181e84b1f]
165. Gollamudi R, Ghalib MH, Desai KK, Chaudhary I, Wong B, Einstein M, Coffey M, Gill GM, Mettinger K, Mariadason JM, Mani S, Goel S. Intravenous administration of Reolysin, a live replication competent RNA virus is safe in patients with advanced solid tumors. Invest New Drugs 2010; 28: 641-649 [PMID: 19572105 DOI: 10.1007/s10637-009-9279-8]
166. Vasef MA, Ross JS, Cohen MB. Telomerase activity in human solid tumors. Diagnostic utility and clinical applications. Am J Clin Pathol 1999; 112: S68-S75 [PMID: 10396302]
167. Suehara N, Mizumoto K, Kusumoto M, Niiyama H, Ogawa T, Yamaguchi K, Yokohata K, Tanaka M. Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer. Am J Gastroenterol 1998; 93: 1967-1971 [PMID: 9772067 DOI: 10.1111/j.1572-0241.1998.00557.x]
168. Bernhardt SL, Gjertsen MK, Trachsel S, Møller M, Eriksen JA, Meo M, Buanes T, Gaudernack G. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer 2006; 95: 1474-1482 [PMID: 17060934 DOI: 10.1038/sj.bjc.6603437]
169. Buanes T, Maurel J, Liauw W, Hebbar M, Nemunaitis J. A randomized phase II study of gemcitabine(G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreas cancer. J Clin Oncol 2009; 27: Abstr 4601
170. GV1001 and Gemcitabine in Sequential Combination to Gemcitabine Monotherapy in Pancreatic Cancer. Available from: URL: http://clinicaltrials.gov/ct2/show/NCT00358566
171. Middleton GW, Valle JW, Wadsley J Propper D, Coxon FY, Ross PJ, Madhusudan S, Roques T, Cunningham D, Corrie P, Greenhalf W, Shaw V, Cox TF, Silcocks P, Nanson G, Neoptolemos JP. A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. ASCO Meeting Abstracts 2013; LBA4004
172. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer SM, Tàmas K, Kornek GV, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W. 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: 2212-2217 [PMID: 17538165 DOI: 10.1200/JCO.2006.09.0886]
173. Final-Results-Phase-III-TeloVac-Trial-Pancreatic, 2013. Press release. Available from: URL: http://www.businesswire.com/news/home/ 20130608005934 /en/
174. Ishizaki H, Manuel ER, Song GY, Srivastava T, Sun S, Diamond DJ, Ellenhorn JD. Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model. Cancer Immunol Immunother 2011; 60: 99-109 [PMID: 20960189 DOI: 10.1007/s00262-010-0923-0]
175. Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res 1994; 54: 2856-2860 [PMID: 7514493]
176. Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, Warnick E, Whiteside T, Osborne J, Kim H, Day R, Troetschel M, Finn OJ. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother 2005; 54: 254-264 [PMID: 15372205 DOI: 10.1007/s00262-004-0581-1]
177. Rong Y, Qin X, Jin D, Lou W, Wu L, Wang D, Wu W, Ni X, Mao Z, Kuang T, Zang YQ, Qin X. A phase I pilot trial of MUC1-peptidepulsed dendritic cells in the treatment of advanced pancreatic cancer. Clin Exp Med 2012; 12: 173-180 [PMID: 21932124 DOI: 10.1007/s10238-011-0159-0]
178. Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, Kim DW, Marshall J. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med 2007; 5: 60 [PMID: 18039393 DOI: 10.1186/1479-5876-5-60]
179. Therion Reports Results of Phase 3 PANVAC-VF Trial and Announces Plans for Company Sale. PR Newswire 28 June. Available from: URL: http://www.prnewswire.com/news-releases/therion-reports-results-of-phase-3-panvac-vf-trial-and-announcesplans-for-companysale-56997582.html
180. Miyazawa M, Ohsawa R, Tsunoda T, Hirono S, Kawai M, Tani M, Nakamura Y, Yamaue H. Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer Sci 2010; 101: 433-439 [PMID: 19930156 DOI: 10.1111/j.1349-7006.2009.01416.x]
181. Yanagimoto H, Shiomi H, Satoi S, Mine T, Toyokawa H, Yamamoto T, Tani T, Yamada A, Kwon AH, Komatsu N, Itoh K, Noguchi M. A phase II study of personalized peptide vaccination combined with gemcitabine for non-resectable pancreatic cancer patients. Oncol Rep 2010; 24: 795-801 [PMID: 20664989]
182. Showalter SL, Huang YH, Witkiewicz A, Costantino CL, Yeo CJ, Green JJ, Langer R, Anderson DG, Sawicki JA, Brody JR. Nanoparticulate delivery of diphtheria toxin DNA effectively kills Mesothelin expressing pancreatic cancer cells. Cancer Biol Ther 2008; 7: 1584-1590 [PMID: 19039293 DOI: 10.4161/cbt.7.10.6562]
183. Oki Y, Younes A. Heat shock protein-based cancer vaccines. Expert Rev Vaccines 2004; 3: 403-411 [PMID: 15270645 DOI: 10.1586/14760584.3.4.403]
184. Maki RG, Livingston PO, Lewis JJ, Janetzki S, Klimstra D, Desantis D, Srivastava PK, Brennan MF. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci 2007; 52: 1964-1972 [PMID: 17420942 DOI: 10.1007/s10620-006-9205-2]
185. Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, Sunamura M, Yonemitsu Y, Shimodaira S, Koido S, Homma S, Okamoto M. Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas 2012; 41: 195-205 [PMID: 21792083 DOI: 10.1097/MPA.0b013e31822398c6]
186. Kobayashi M, Shimodaira S, Nagai K, Ogasawara M, Takahashi H, Abe H, Tanii M, Okamoto M, Tsujitani S, Yusa S, Ishidao T, Kishimoto J, Shibamoto Y, Nagaya M, Yonemitsu Y. Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis. Cancer Immunol Immunother 2014; 63: 797-806 [PMID: 24777613 DOI: 10.1007/s00262-014-1554-7]
187. Pei Q, Pan J, Zhu H, Ding X, Liu W, Lv Y, Zou X, Luo H. Gemcitabine-treated pancreatic cancer cell medium induces the specific CTL antitumor activity by stimulating the maturation of dendritic cells. Int Immunopharmacol 2014; 19: 10-16 [PMID: 24389382 DOI: 10.1016/j.intimp.2013.12.022]
188. Bauer C, Sterzik A, Bauernfeind F, Duewell P, Conrad C, Kiefl R, Endres S, Eigler A, Schnurr M, Dauer M. Concomitant gemcitabine therapy negatively affects DC vaccine-induced CD8(+) T-cell and B-cell responses but improves clinical efficacy in a murine pancreatic carcinoma model. Cancer Immunol Immunother 2014; 63: 321-333 [PMID: 24384835 DOI: 10.1007/s00262-013-1510-y]
189. Morse MA, Nair SK, Boczkowski D, Tyler D, Hurwitz HI, Proia A, Clay TM, Schlom J, Gilboa E, Lyerly HK. The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer. Int J Gastrointest Cancer 2002; 32: 1-6 [PMID: 12630764 DOI: 10.1385/IJGC:32:1:1]
190. Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, Gaudernack G. hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011; 60: 809-818 [PMID: 21365467 DOI: 10.1007/s00262-011-0991-9]
191. Hirooka Y, Itoh A, Kawashima H, Hara K, Nonogaki K, Kasugai T, Ohno E, Ishikawa T, Matsubara H, Ishigami M, Katano Y, Ohmiya N, Niwa Y, Yamamoto K, Kaneko T, Nieda M, Yokokawa K, Goto H. A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas 2009; 38: e69-e74 [PMID: 19276867 DOI: 10.1097/MPA.0b013e318197a9e3]
192. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O' Dwyer PJ, Vonderheide RH. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331: 1612-1616 [PMID: 21436454 DOI: 10.1126/science.1198443]
193. Yang B, He Y, Sun DL, Zou Y, Qin XH, Huang BH. [Specific immune against pancreatic cancer induced by dendritic cells pulsed with mutant K-ras peptide]. Zhonghua Yi Xue Zazhi 2008; 88: 1956-1960 [PMID: 19062734]
194. Schmidt J, Ryschich E, Sievers E, Schmidt-Wolf IG, Büchler MW, Märten A. Telomerase-specific T-cells kill pancreatic tumor cells in vitro and in vivo. Cancer 2006; 106: 759-764 [PMID: 16369992 DOI: 10.1002/cncr.21655]
195. Yokokawa J, Palena C, Arlen P, Hassan R, Ho M, Pastan I, Schlom J, Tsang KY. Identification of novel human CTL epitopes and their agonist epitopes of mesothelin. Clin Cancer Res 2005; 11: 6342-6351 [PMID: 16144939 DOI: 10.1158/1078-0432.CCR-05-0596]
196. Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, Shi Y, Abbruzzese J, Konopleva M, Andreeff M, Marini FC. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy 2010; 12: 615-625 [PMID: 20230221 DOI: 10.3109/14653241003631815]
197. Moniri MR, Dai LJ, Warnock GL. The challenge of pancreatic cancer therapy and novel treatment strategy using engineered mesenchymal stem cells. Cancer Gene Ther 2014; 21: 12-23 [PMID: 24384772 DOI: 10.1038/cgt.2013.83]