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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2.2

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019031642
pages 157-177

Newer Trends in Pancreatic Cancer Treatment: Genetic Alterations and the Role of Immune Therapeutic and Targeted Therapies

Ishtiaq Hussain
Abington Hospital−Jefferson Health, Abington, Pennsylvania; Department of Gastroenterology, Cleveland Clinic, Weston, FL 33331
Mamoon Ur Rashid
Department of Gastroenterology, Cleveland Clinic, Weston, Florida; Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Deepika Sarvepalli
Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Asad ur Rahman
Department of Gastroenterology, Cleveland Clinic, Weston, FL 33331
Waqas Ullah
Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa, Pakistan; Abington Hospital - Jefferson Health, Abington, PA 19001, USA
Hasan Badar
Department of Gastroenterology, Cleveland Clinic, Weston, FL 33331
Sundas Jehanzeb
Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
Abdul Kareem Khan
Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Muhammad Talha Khan
Department of Internal Medicine, Carle Hospital, Urbana, IL 61801
Muhammad Muzammil
Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
Sarfraz Ahmad
Department of Gynecologic Oncology, AdventHealth Cancer Institute, Orlando, FL 32804


Pancreatic cancer prognosis has remained poor and no significant improvement has been achieved over the past two decades. A number of genetic alterations are found in pancreatic cancer with a complex genome and proteome that needs further research investigation and discovery. There is an urgent need for innovative research findings that would increase the 5-year survival rate in patients with pancreatic ductal carcinoma, which in fact has seen only small increments over the past two decades. Targeting the tumor and modifying the stroma could help improve therapy responses. Genomic medicine is useful in a fraction of patients currently; however, the newer proteomic approaches are potentially more likely to help the majority of patients in the future. Future treatments of pancreatic cancer will likely be based on the development of novel therapies per genomic and proteomic identifications of cellular/immunological processes and molecular pathways as therapeutic targets. Herein, we systematically review the newer trends in pancreatic cancer treatment with emphasis on the genetic alterations and role of immune therapeutics and targeted therapies.


  1. Jenne DE, Reomann H, Nezu JI, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine 15 threoninekinase. Nature Gen. 1998 Jan;18(1):38.

  2. Haluska FG, Hodi FS. Molecular genetics of familial cutaneous melanoma. J Clin Oncol. 1998 Feb;16(2):670-82.

  3. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014 Sep 11;371(11):1039-49.

  4. Grover S, Syngal S. Hereditary pancreatic cancer. Gastroenterology. 2010 Oct 1;139(4):1076-80.

  5. Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer 18. Res. 2000 Jan 15;60(2):409-16.

  6. Couch FJ, Johnson MR, Rabe K, Boardman L, McWilliams R, De Andrade M, Petersen G. Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 2005 Jan 15;65(2):383-6.

  7. Ferrone CR, Levine DA, Tang LH, Allen PJ, Jarnagin 19. W, Brennan MF, Offit K, Robson ME. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol. 2009 Jan 20;27(3):433.

  8. Salo-Mullen EE, O'Reilly EM, Kelsen DP, Ashraf AM, Lowery MA, Yu KH, Reidy DL, Epstein AS, Lincoln A, Saldia A, Jacobs LM. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer. 2015 Dec 15;121(24):4382-8.

  9. Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015 Mar 1;148(3):556-64.

  10. Rishi A, Goggins M, Wood LD, Hruban RH. Pathological and molecular evaluation of pancreatic neoplasms. In: Seminars in oncology. Philadelphia, PA: WB Saunders; 2015 Feb 1;42(1):28-39.

  11. Chandana S, Mahadevan D. Translational advances and novel therapies for pancreatic ductal adenocarcinoma: hope or hype?. Exp Rev Mol Med. 2009 Nov;11.

  12. Woollard PM, Mehta NA, Vamathevan JJ, Van Horn S, Bonde BK, Dow DJ. The application of next-generation sequencing technologies to drug discovery and development. Drug Discov Today. 2011 Jun 1;16(11- 12):512-9.

  13. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008 Sep 26;321(5897):1801-6.

  14. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012 Nov;491(7424):399.

  15. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015 Feb;518(7540):495.

  16. Roberts NJ, Norris AL, Petersen GM, Bondy ML, Brand R, Gallinger S, Kurtz RC, Olson SH, Rustgi AK, Schwartz AG, Stoffel E. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 2016 Feb 1;6(2):166-75.

  17. Dreyer SB, Chang DK, Bailey P, Biankin AV. Pancreatic cancer genomes: implications for clinical management and therapeutic development. Clin Cancer Res. 2017; 23(7):1638-46. doi: 10'1158/1078-0432'CCR-16-2411.

  18. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010 Jan 19;17(1):98-110.

  19. Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nature Commun. 2015 Apr 9;6:6744.

  20. Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007 Apr 1;6(4):1186-97.

  21. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, Smyla JK. Virtual microdissection identifies distinct tumor-and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nature Gen. 2015 Oct;47(10):1168.

  22. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nature Med. 2011 Apr;17(4):500.

  23. Burris H3, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Christine Cripps M, Portenoy RK, Storniolo AM, Tarassoff P. 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 Jun 1;15(6):2403-13.

  24. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25.

  25. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703.

  26. Ouyang G, Liu Z, Huang S, Li Q, Xiong L, Miao X, Wen Y. Gemcitabine plus cisplatin versus gemcitabine alone in the treatment of pancreatic cancer: a meta-analysis. World J Surg Oncol. 2016 Dec;14(1):59.

  27. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Kohne CH. 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. 38. 2007 Jun 1;25(16):2212-7.

  28. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in 39. patients with advanced pancreatic cancer. J Clin Oncol. 2009 Oct 26;27(33):5513-8.

  29. Scheithauer W, Schull B, Ulrich-Pur H, Schmid K, Raderer M, Haider K, Kwasny W, Depisch D, Schneeweiss B, Lang F, Kornek GV. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol. 2003 Jan 1;14(1):97-104.

  30. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 42. 3 trial. Lancet. 2016 Feb 6;387(10018):545-57.

  31. Hunter JC, Gurbani D, Ficarro SB, Carrasco MA, Lim SM, Choi HG, Xie T, Marto JA, Chen Z, Gray NS, Westover KD. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc Natl Acad Sci USA. 2014 Jun 17;111(24):8895-900.

  32. Macdonald JS, McCoy S, Whitehead RP, Iqbal S, Wade JL, Giguere JK, Abbruzzese JL. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs. 2005 Oct 1;23(5):485-7.

  33. Van Cutsem E, Van De Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004 Apr 15;22(8):1430-8.

  34. Yuan TL, Fellmann C, Lee CS, Ritchie CD, Thapar V, Lee LC, Hsu DJ, Grace D, Carver JO, Zuber J, Luo J. Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov. 2014 Oct 1;4(10):1182-97.

  35. Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, Cai W, Chirino LM, Yang GR, Bronson R, Crowley DG. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci USA. 2014 Aug 26;111(34):E3553.

  36. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell. 2002 Sep 1;2(3):243-7.

  37. Khvalevsky EZ, Gabai R, Rachmut IH, Horwitz E, Brunschwig Z, Orbach A, Shemi A, Golan T, Domb AJ, Yavin E, Giladi H. Mutant KRAS is a druggable target for pancreatic cancer. Proc Natl Acad Sci USA. 2013 Dec 17;110(51):20723-8.

  38. Golan T, Khvalevsky EZ, Hubert A, Gabai RM, Hen N, Segal A, Domb A, Harari G, David EB, Raskin S, Goldes Y. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget. 2015 Sep 15;6(27):24560.

  39. Pecot CV, Wu SY, Bellister S, Filant J, Rupaimoole R, Hisamatsu T, Bhattacharya R, Maharaj A, Azam S, Rodriguez-Aguayo C, Nagaraja AS. Therapeutic silencing of KRAS using systemically delivered siRNAs. Mol Cancer Ther. 2014 Dec 1;13(12):2876-85.

  40. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, Settleman J. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009 Jun 2;15(6):489-500.

  41. Muzumdar MD, Chen PY, Dorans KJ, Chung KM, Bhutkar A, Hong E, Noll EM, Sprick MR, Trumpp A, Jacks T. Survival of pancreatic cancer cells lacking KRAS function. Nature Commun. 2017 Oct 23;8(1):1090.

  42. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D. 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 May 20;25(15):1960-6.

  43. Chou A, Waddell N, Cowley MJ, Gill AJ, Chang DK, Patch AM, Nones K, Wu J, Pinese M, Johns AL, Miller DK. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 2013 Aug;5(8):78.

  44. Harder J, Ihorst G, Heinemann V, Hofheinz R, Moehler M, Buechler P, Kloeppel G, Rocken C, Bitzer M, Boeck S, Endlicher E. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012 Mar;106(6):1033.

  45. Zhang H, Hylander BL, LeVea C, Repasky EA, 54. Straubinger RM, Adjei AA, Ma WW. Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. Br J Cancer. 2014 Jan;110(2):320.

  46. Ma WW, Fetterly G, LeVea C, Zhao Y, Dy GK, Iyer R, Tan W, Brady W, Whitworth A, Adjei AA. 2315 A phase Ib study of the FGFR/VEGFR inhibitor dovitinib (D) combined with gemcitabine (G) and capecitabine (C) in advanced pancreatic cancer patients. Eur J Cancer. 2015 Sep 1;51:S438.

  47. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018 Feb 22;378(8):731-9.

  48. Pishvaian MJ, Rolfo CD, Liu SV, Multani PS, Chow Maneval E, Garrido-Laguna I. Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions. J Clin Oncol. 2018;36(4 Suppl):521-521. doi: 10.1200/JC0.2018.36.4_suppl.521.

  49. Singhi AD, Ali SM, Lacy J, Hendifar A, Nguyen K, Koo J, Chung JH, Greenbowe J, Ross JS, Nikiforova MN, Zeh HJ. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J Natl Comp Cancer Net. 2017 May 1;15(5):555-62.

  50. Kessler ER, Eckhardt SG, Pitts TM, Bradshaw-Pierce EL, O'byrant CL, Messersmith WA, Nallapreddy S, Weekes C, Spratlin J, Lieu CH, Kane MA. Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers. Invest New Drugs. 2016 Apr 1;34(2):176-83.

  51. Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017 Apr 1;18(4):486-99.

  52. 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 Aug 1;50(12):2072-81.

  53. 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(3):1216-23.

  54. Pettazzoni P, Viale A, Shah P, Carugo A, Ying H, Wang H, Genovese G, Seth S, Minelli R, Green T, Huang-Hobbs E. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res. 2015 Mar 15;75(6):1091-101.

  55. Mirzoeva OK, Collisson EA, Schaefer PM, Hann B, Hom YK, Ko AH, Korn WM. Subtype-specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma. Mol Cancer Ther. 2013 Oct 1;12(10):2213-25.

  56. Brauswetter D, Gurbi B, Varga A, Varkondi E, Schwab R, Banhegyi G, Fabian O, Keri G, Valyi-Nagy I, Petak I. Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. PLoS One. 2017 Sep 28;12(9):e0185687.

  57. Kordes S, Klumpen HJ, Weterman MJ, Schellens JH, Richel DJ, Wilmink JW. Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2015 Jun 1;75(6):1135-41.

  58. Chung V, McDonough S, Philip PA, Cardin D, Wang- Gillam A, Hui L, Tejani MA, Seery TE, Dy IA, Al Baghdadi T, Hendifar AE. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):516-22.

  59. Klumpen HJ, Queiroz KC, Spek CA, Van Noesel CJ, Brink HC, De Leng WW, De Wilde RF, Mathus-Vliegen EM, Offerhaus GJ, Alleman MA, Westermann AM. mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome. J Clin Oncol. 2011 Feb 20;29(6):e150.

  60. Driscoll DR, Karim SA, Sano M, Gay DM, Jacob W, Yu J, Mizukami Y, Gopinathan A, Jodrell DI, Evans TJ, Bardeesy N. mTORC2 signaling drives the development and progression of pancreatic cancer. Cancer Res. 2016 Dec 1;76(23):6911-23.

  61. Conway JR, Warren SC, Herrmann D, Murphy KJ, Cazet AS, Vennin C, Shearer RF, Killen MJ, Magenau A, Melenec P, Pinese M. Intravital imaging to monitor therapeutic response in moving hypoxic regions resistant to PI3K pathway targeting in pancreatic cancer. Cell Rep. 2018 Jun 12;23(11):3312-26.

  62. Stine RR, Matunis EL. JAK-STAT signaling in stem cells. In: Transcriptional and translational regulation of stem cells. Dordrecht, the Netherlands: Springer; 2013. p. 247-267.

  63. Fukuda A, Wang SC, Morris IV JP, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011 Apr 12;19(4):441-55.

  64. Denley SM, Jamieson NB, McCall P, Oien KA, Morton JP, Carter CR, Edwards J, McKay CJ. Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J Gastro Surg. 2013 May 1;17(5):887-98.

  65. Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, Chen X, Walsh AJ, Skala MC, Moses HL, Merchant NB. STAT3 mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology. 2015 Dec;149(7):1932.

  66. Bekaii-Saab TS, Starodub A, El-Rayes BF, O'Neil BH, Shahda S, Ciombor KK, Noonan AM, Hanna WT, Sehdev A, Shaib WL, Mikhail S. A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). J Clin Oncol. 2017;35(15 Suppl):4106-4106. doi: 10.1200/JC0.2017.35.15_suppl.4106.

  67. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 2016 Feb 9;14(5):979-90.

  68. Chantrill LA, Nagrial AM, Watson C, Johns AL, Martyn-Smith M, Simpson S, Mead S, Jones MD, Samra JS, Gill AJ, Watson N. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. Clin Cancer Res. 2015 May 1;21(9):2029-37.

  69. Kim H, Saka B, Knight S, Borges M, Childs E, Klein A, Wolfgang C, Herman J, Adsay VN, Hruban RH, Goggins M. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res. 2014 Apr 1;20(7):1865-72.

  70. Lowery MA, Kelsen DP, Capanu M, Smith SC, Lee JW, Stadler ZK, Moore MJ, Kindler HL, Golan T, Segal A, Maynard H. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018 Jan 1;89:19-26.

  71. O'Reilly EM, Lee JW, Lowery MA, Capanu M, Stadler ZK, Moore MJ, Dhani N, Kindler HL, Estrella H, Maynard H, Golan T. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018 Apr 1;124(7):1374-82.

  72. Okazaki T, Jiao L, Chang P, Evans DB, Abbruzzese JL, Li D. Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer. Clin Cancer Res. 2008 Apr 1;14(7):2042-8.

  73. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013 Jan 1;62(1):112-20.

  74. Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, Tjulandin SA, Gladkov OA, Holcombe RF, Korn R, Raghunand N. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016 Jun 15;22(12):2848-54.

  75. Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, Braiteh F, Ritch PS, Zalupski MM, Bahary N, Oberstein PE. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018 Feb 1;36(4):359-66.

  76. Ramanathan RK, McDonough S, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, Thumar JR, Chiorean EG, Shields AF, Behl D, Mehan PT. A phase IB/II randomized study of mFOLFIRINOX (mFFOX)+ pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT# 01959139). J Clin Oncol. 2018;36(4 Suppl):208-208. doi: 10.1200/JCO.2018.36.4_suppl.208.

  77. Vennin C, Chin VT, Warren SC, Lucas MC, Herrmann D, Magenau A, Melenec P, Walters SN, del Monte-Nieto G, Conway JR, Nobis M. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Trans Med. 2017 Apr 5;9(384):eaai8504.

  78. Qi J. Bromodomain and extraterminal domain inhibitors (BETi) for cancer therapy: chemical modulation of chromatin structure. Cold Spring Harbor Perspectives Biol. 2014 Dec 1;6(12):a018663.

  79. Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nature Med. 2015 Oct;21(10):1163.

  80. Sahai V, Kumar K, Knab LM, Chow CR, Raza SS, Bentrem DJ, Ebine K, Munshi HG. BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen. Molecular cancer therapeutics. 2014 Jul 1;13(7):1907-17.

  81. Yamamoto K, Tateishi K, Kudo Y, Hoshikawa M, Tanaka M, Nakatsuka T, Fujiwara H, Miyabayashi K, Takahashi R, Tanaka Y, Ijichi H. Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer. Oncotarget. 2016 Sep 20;7(38):61469.

  82. Binker MG, Binker-Cosen AA, Gaisano HY, de Cosen RH, Cosen-Binker LI. TGF-P1 increases invasiveness of SW1990 cells through Rac1/ROS/NF-KB/IL-6/ MMP-2. Biochem Biophys Res Commun. 2011 Feb 4;405(1):140-5.

  83. Binker-Cosen MJ, Richards D, Oliver B, Gaisano HY, Binker MG, Cosen-Binker LI. Palmitic acid increases invasiveness of pancreatic cancer cells AsPC-1 through TLR4/ROS/NF-KB/MMP-9 signaling pathway. Biochem Biophys Res Communs. 2017 Feb 26;484(1):152-8.

  84. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA, Marimastat Pancreatic Cancer Study Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001 Aug 1;19(15):3447-55.

  85. 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 Jul;87(2):161.

  86. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D. 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 Sep 1;21(17):3296-302.

  87. Van Cutsem E, Lenz HJ, Furuse J, Tabernero J, Heinemann V, Ioka T, Bazin I, Ueno M, Csoszi T, Wasan H, Melichar B. Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study. J Clin Oncol. 2016;34(4 Suppl):193-193. doi: 10.1200/ jco.2016.34.4_suppl.193.

  88. Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, Pilarsky C, Jodrell DI, Spong SM, Tuveson DA. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci USA. 2013 Jul 23;110(30):12325-30.

  89. Picozzi VJ, Pipas JM, Koong A, Giaccia A, Bahary N, Krishnamurthi SS, Lopez CD, O'Dwyer PJ, Modelska K, Carney M, Hernandez H. FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF), with gemcitabine/erlotinib (G/E) in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). J Cancer Clin Trials. 2017;2(123):1-8.

  90. Picozzi VJ, Rocha FG, Helton S, Pishvaian MJ, Jackson PG, Mody K, Asbun H, Carney M, Etheridge T, Neff TB, Porter S. Randomized, open-abel trial of gemcitabine/nab-paclitaxel (G/NP)+-pamrevlumab (P) as neoadjuvant chemotherapy in locally advanced, unresectable pancreatic cancer (LAPC). J Clin Oncol. 2017;35(4 Suppl):365-365.

  91. Pothula SP, Xu Z, Goldstein D, Biankin AV, Pirola RC, Wilson JS, Apte MV. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br J Cancer. 2016 Feb;114(3):269-280.

  92. Pothula SP, Xu Z, Goldstein D, Merrett N, Pirola RC, Wilson JS, Apte MV. Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer. Oncotarget. 2017 Sep 29;8(44):76722.

  93. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Rev Immunol. 2013 Apr;13(4):227-242.

  94. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar;531(7592):47-52.

  95. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20.

  96. Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, Wells DK. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017 Nov;551(7681):512-16.

  97. Connor AA, Denroche RE, Jang GH, Timms L, Kalimuthu SN, Selander I, McPherson T, Wilson GW, Chan-Seng-Yue MA, Borozan I, Ferretti V. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol. 2017 Jun 1;3(6):774-83.

  98. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, Rosenberg SA. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010 Oct 1;33(8):828-33.

  99. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz Jr 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 (Hagerstown, MD.: 1997). 2013 Sep;36(7):382.

  100. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014 Jul 1;153(1):145-52.

  101. Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao S, Azuma M, Yagita H. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 2009 Oct 1;35(4):741-9.

  102. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 113. Jun 28;366(26):2455-65.

  103. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leuk Biol. 2000;67(1):2-17.

  104. He S, Zhao H, Fei M, Wu Y, Wang L, Zhu X, Li D. Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro. Oncol Rep. 2012 Jul 1;28(1):262-8.

  105. 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 Nov 15;19(22):6286-95.

  106. Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, Wang-Gillam A. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013 Jul 1;19(13):3404-15.

  107. Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, Toriola AT, Nieman RK, Worley LA, Yano M, Fowler KJ. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016 May 1;17(5):651-62.

  108. Noel M, Lowery M, Ryan D, Wolpin B, BullockA, Britten C, Jin B, Ganguly BJ, Taylor CT, Yin D, Wunderlich DA. 750PPhase Ib study of PF-04136309 (an oral CCR2 inhibitor) in combination with nab-paclitaxel/ gemcitabine in first-line treatment of metastatic pancreatic adenocarcinoma. Ann Oncol. 2017 Sep 1;28(Suppl 5).

  109. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2, 3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 2005 Mar;11(3):312.

  110. Bahary N, Garrido-Laguna I, Cinar P, O'Rourke MA, Somer BG, Nyak-Kapoor A, Lee JS, Munn D, Kennedy EP, Vahanian NN. Phase 2 trial of the indoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. J Clin Oncol. 2016 May 20;34(15):3020.

  111. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res. 2007 Feb 1;67(3):1030-7.

  112. Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, di Magliano MP, Simeone DM. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011 Dec 1;141(6):2218-27.

  113. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007 Sep 13;1(3):313-23.

  114. Rasheed Z, Wang Q, Matsui W. Isolation of stem cells from human pancreatic cancer xenografts. J Visual Exper (JoVE). 2010 Sep 26(43):e2169.

  115. Bailey JM, Alsina J, Rasheed ZA, McAllister FM, Fu YY, Plentz R, Zhang H, Pasricha PJ, Bardeesy N, Matsui W, Maitra A. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology. 2014 Jan 1;146(1):245-56.

  116. Fujiwara K, Ohuchida K, Sada M, Horioka K, Ulrich III CD, Shindo K, Ohtsuka T, Takahata S, Mizumoto K, Oda Y, Tanaka M. CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells. PLoS One. 2014 Sep 15;9(9):e107247.

  117. Bao B, Azmi AS, Aboukameel A, Ahmad A, Bolling-Fischer A, Sethi S, Ali S, Li Y, Kong D, Banerjee S, Back J. Pancreatic cancer stem-like cells display aggressive behavior mediated via activation of FoxQl. J Bio Chem. 2014 May 23;289(21):14520-33.

  118. Skoda J, Hermanova M, Loja T, Nemec P, Neradil J, Karasek P, Veselska R. Co-expression of cancer stem cell markers corresponds to a pro-tumorigenic expression profile in pancreatic adenocarcinoma. PLoS One. 2016 Jul 14;11(7):e0159255.

  119. Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature Med. 2013 Nov;19(11):1410-22.

  120. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008 Sep;455(7211):406.

  121. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015 Dec 20;33(36):4284.

  122. Ko AH, LoConte N, Tempero MA, Walker EJ, Kelley RK, Lewis S, Chang WC, Kantoff E, Vannier MW, Catenacci DV, Venook AP. A phase I study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas. 2016 Mar;45(3):370.

  123. Gao J, Long B, Wang Z. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res. 2017;7(2):173-86.

  124. Buchler P, Gazdhar A, Schubert M, Giese N, Reber HA, Hines OJ, Giese T, Ceyhan GO, Muller M, Buchler MW, Friess H. The Notch signaling pathway is related to neurovascular progression of pancreatic cancer. Ann Surg. 2005 Dec;242(6):791.

  125. Doucas H, Mann CD, Sutton CD, Garcea G, Neal CP, Berry DP, Manson MM. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of 133 STAT3 and phosphorylated Akt. J Surg Oncol. 2008 Jan 1;97(1):63-8.

  126. Yao J, Qian C. Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway. Med Oncol. 2010 Sep 1;27(3):1017-22.

  127. 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 Aug 1;32(4):739-45.

  128. Zhang Y, Morris JP, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M, di Magliano MP. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 2013 Aug 1;73(15):4909-22.

  129. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/p-catenin signaling in gastrointestinal cancers. Gastroenterology. 2012 Feb 1;142(2):219-32.

  130. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 2013 Jul 30;110(31):12649-54.

  131. Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, Lam A. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA. 2012 Jul 17;109(29):11717-22.

  132. Geng R, Li Z, Li S, Gao J. Proteomics in pancreatic cancer research. Int J Proteom. 2011. doi: 10.1155/2011/365350.

  133. Jimenez-Luna C, Torres C, Ortiz R, Dieguez C, Martinez-Galan J, Melguizo C, Prados JC, Caba O. Proteomic biomarkers in body fluids associated with pancreatic cancer. Oncotarget. 2018 Mar 27;9(23):16573.

  134. Humphery-Smith I. A human proteome project with a beginning and an end. Proteomics. 2004 Sep;4(9):2519-21.

  135. Mueller M, Martens L, Apweiler R. Annotating the human proteome: beyond establishing a parts list. Biochimica Biophysica Acta (BBA)-Proteins Proteomics. 2007 Feb 1;1774(2):175-91.

  136. Tape CJ, Ling S, Dimitriadi M, McMahon KM, Worboys JD, Leong HS, Norrie IC, Miller CJ, Poulogiannis G, Lauffenburger DA, J0rgensen C. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell. 2016 May 5;165(4):910-20.

  137. Wang X, Niu J, Li J, Shen X, Shen S, Straubinger RM, Qu J. Temporal effects of combined birinapant and paclitaxel on pancreatic cancer cells investigated via large-scale, ion-current-based quantitative proteomics (IonStar). Mol Cell Proteom. 2018 Apr 1;17(4):655-71.

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