308
Views
27
CrossRef citations to date
0
Altmetric
Review

The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities

ORCID Icon, , &
Pages 131-148 | Received 23 Jul 2017, Accepted 12 Dec 2017, Published online: 19 Dec 2017

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. Pubmed PMID: 28055103 DOI: 10.3322/caac.21387
  • American Cancer Society. Cancer facts and figures 2017. Atlanta (GA): American Cancer Society; 2017.
  • Heinemann V, Boeck S. Perioperative management of pancreatic cancer. PubMed PMID: 18790965. Ann Oncol. 2008 Sep;19 Suppl 7:vii273–8
  • Sjoquist KM, Chin VT, Chantrill LA, et al. Personalising pancreas cancer treatment: when tissue is the issue. World J Gastroenterol. 2014 Jun 28;20(24):7849–7863. PubMed PMID: 24976722; PubMed Central PMCID: PMCPMC4069313.
  • Cress RD, Yin D, Clarke L, et al. Survival among patients with adenocarcinoma of the pancreas: a population-based study (United States). Cancer Causes Control. 2006 May;17(4):403–409. PubMed PMID: 16596292.
  • Alexakis N, Halloran C, Raraty M, et al. Current standards of surgery for pancreatic cancer. Br J Surg. 2004 Nov;91(11):1410–1427. PubMed PMID: 15499648.
  • Schrag D, Archer L, Wang X, et al. A patterns-of-care study of post-progression treatment (Rx) among patients (pts) with advanced pancreas cancer (APC) after gemcitabine therapy on Cancer and Leukemia Group B (CALGB) study #80303. J Clin Oncol. 2007;25(18_suppl):4524.
  • Kim HJ, Kim MH, Myung SJ, et al. A new strategy for the application of CA19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J Gastroenterol. 1999 Jul;94(7):1941–1946. PubMed PMID: 10406263.
  • Steinberg W. The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990 Apr;85(4):350–355. PubMed PMID: 2183589.
  • Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.
  • Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002 Dec;2(12):897–909. PubMed PMID: 12459728.
  • Fang Y, Yao Q, Chen Z, et al. Genetic and molecular alterations in pancreatic cancer: implications for personalized medicine. Med Sci Monit. 2013 Oct 31;19:916–926. PubMed PMID: 24172537; PubMed Central PMCID: PMCPMC3818103.
  • Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011 Oct 13;11(11):761–774. PubMed PMID: 21993244; PubMed Central PMCID: PMCPMC3632399.
  • Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003 Dec;4(6):437–450. PubMed PMID: 14706336.
  • Rhim AD, Stanger BZ. Molecular biology of pancreatic ductal adenocarcinoma progression: aberrant activation of developmental pathways. Prog Mol Biol Transl Sci. 2010;97: 41–78. PubMed PMID: 21074729; PubMed Central PMCID: PMCPMC3117430.
  • Hustinx SR, Leoni LM, Yeo CJ, et al. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol. 2005 Jul;18(7):959–963. PubMed PMID: 15832197.
  • Sharpless NE, DePinho RA. Cancer: crime and punishment. Nature. 2005 Aug 04;436(7051):636–637. PubMed PMID: 16079829.
  • Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994 Jun 01;54(11):3025–3033. PubMed PMID: 8187092.
  • Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997 May 01;57(9):1731–1734. PubMed PMID: 9135016.
  • Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996 Jan 19;271(5247):350–353. PubMed PMID: 8553070.
  • Cleaver JE, Lam ET, Revet I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet. 2009 Nov;10(11):756–768. PubMed PMID: 19809470.
  • Lieber MR. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008 Jan 04;283(1):1–5. PubMed PMID: 17999957.
  • Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008 Aug;9(8):619–631. PubMed PMID: 18626472.
  • Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006 May;7(5):335–346. PubMed PMID: 16612326.
  • Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010 Mar;11(3):196–207. PubMed PMID: 20177395; PubMed Central PMCID: PMCPMC3261768.
  • Maginn EN, De Sousa CH, Wasan HS, et al. Opportunities for translation: targeting DNA repair pathways in pancreatic cancer. Biochim Biophys Acta. 2014 Aug;1846(1):45–54. PubMed PMID: 24727386.
  • Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002 Jul 01;62(13):3789–3793. PubMed PMID: 12097290.
  • Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171–182. PubMed PMID: 11832208.
  • Nikkila J, Parplys AC, Pylkas K, et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat Commun. 2013;4:2578, PubMed PMID: 24153426; PubMed Central PMCID: PMCPMC3826652
  • Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011 Jan;10(1):3–8. PubMed PMID: 21135251; PubMed Central PMCID: PMCPMC3307340.
  • Peng G, Lin S-Y-Y. Exploiting the homologous recombination DNA repair network for targeted cancer therapy. World J Clin Oncol. 2011;2(2):73–79.
  • Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012 Jan;2(1):41–46. PubMed PMID: 22585167; PubMed Central PMCID: PMCPMC3676748.
  • Erkan M, Hausmann S, Michalski CW, et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012 Aug;9(8):454–467. PubMed PMID: 22710569.
  • Erkan M, Michalski CW, Rieder S, et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1155–1161. PubMed PMID: 18639493.
  • Hidalgo M. Pancreatic cancer. N Engl J Med. 2010 Apr 29;362(17):1605–1617. PubMed PMID: 20427809.
  • Korc M. Pancreatic cancer-associated stroma production. Am J Surg. 2007 Oct;194(4Suppl):S84–6. PubMed PMID: 17903452; PubMed Central PMCID: PMCPMC2094116.
  • Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998 Jul;43(1):128–133. PubMed PMID: 9771417; PubMed Central PMCID: PMCPMC1727174.
  • Masamune A, Shimosegawa T. Signal transduction in pancreatic stellate cells. PubMed PMID: 19271115 J Gastroenterol. 2009;444:249–260. 10.1007/s00535-009-0013-2
  • Apte MV, Xu Z, Pothula S, et al. Pancreatic cancer: the microenvironment needs attention too!. Pancreatology. 2015 Jul;15(4Suppl):S32–8. PubMed PMID: 25845856. DOI:10.1016/j.pan.2015.02.013
  • Apte MV, Wilson JS, Lugea A, et al. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology. 2013 Jun;144(6):1210–1219. PubMed PMID: 23622130; PubMed Central PMCID: PMCPMC3729446. DOI:10.1053/j.gastro.2012.11.037
  • Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013 Nov;145(5):1121–1132. PubMed PMID: 23891972; PubMed Central PMCID: PMCPMC3896919. DOI:10.1053/j.gastro.2013.07.025
  • Mace TA, Bloomston M, Lesinski GB. Pancreatic cancer-associated stellate cells: a viable target for reducing immunosuppression in the tumor microenvironment. Oncoimmunology. 2013 Jul 01;2(7):e24891. doi:10.4161/onci.24891. PubMed PMID: 24073373; PubMed Central PMCID: PMCPMC3782129.
  • Xu Z, Vonlaufen A, Phillips PA, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 2010 Nov;177(5):2585–2596. PubMed PMID: 20934972; PubMed Central PMCID: PMCPMC2966814. DOI:10.2353/ajpath.2010.090899
  • Patel MB, Pothula SP, Xu Z, et al. The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer. Carcinogenesis. 2014 Aug;35(8):1891–1900. PubMed PMID: 24876152. DOI:10.1093/carcin/bgu122
  • Rucki AA, Zheng L. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J Gastroenterol. 2014 Mar 07;20(9):2237–2246. doi:10.3748/wjg.v20.i9.2237. PubMed PMID: 24605023; PubMed Central PMCID: PMCPMC3942829.
  • Zheng L, Xue J, Jaffee EM, et al. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology. 2013 Jun;144(6):1230–1240. PubMed PMID: 23622132; PubMed Central PMCID: PMCPMC3641650. DOI:10.1053/j.gastro.2012.12.042
  • Porembka MR, Mitchem JB, Belt BA,et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother. 2012 Sep;61(9):1373–1385. PubMed PMID: 22215137; PubMed Central PMCID: PMCPMC3697836. DOI:10.1007/s00262-011-1178-0
  • Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006 Aug 01;108(3):804–811. doi:10.1182/blood-2006-02-002774. PubMed PMID: 16861339.
  • Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008 Oct;18(5):349–355. PubMed PMID: 18467122. DOI:10.1016/j.semcancer.2008.03.004
  • Loos M, Giese NA, Kleeff J, et al. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett. 2008 Sep 08;268(1):98–109. PubMed PMID: 18486325. DOI:10.1016/j.canlet.2008.03.056
  • Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007 Apr 01;13(7):2151–2157. PubMed PMID: 17404099. DOI:10.1158/1078-0432.CCR-06-2746
  • Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer. 2010 Jan;1(1):12–25. DOI:10.1177/1947601909356574. PubMed PMID: 21779425; PubMed Central PMCID: PMCPMC3092176.
  • Shibuya M. Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. BMB Rep. 2008 Apr 30;41(4):278–286. PubMed PMID: 18452647.
  • Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010 Aug 01;28(22):3617–3622. PubMed PMID: 20606091; PubMed Central PMCID: PMCPMC2917317. eng. DOI:10.1200/jco.2010.28.1386
  • Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009 May 01;27(13):2231–2237. PubMed PMID: 19307500. DOI:10.1200/JCO.2008.20.0238
  • Pennacchietti S, Michieli P, Galluzzo M, et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003 Apr;3(4):347–361. PubMed PMID: 12726861.
  • Tsarfaty I, Rong S, Resau JH, et al. The Met proto-oncogene mesenchymal to epithelial cell conversion. Science. 1994 Jan 07;263(5143):98–101. PubMed PMID: 7505952.
  • Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009 Jun;119(6):1420–1428. DOI:10.1172/JCI39104. PubMed PMID: 19487818; PubMed Central PMCID: PMCPMC2689101.
  • Avan A, Caretti V, Funel N, et al. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. Cancer Res. 2013 Nov 15;73(22):6745–6756. PubMed PMID: 24085787. DOI:10.1158/0008-5472.CAN-13-0837
  • Brandes F, Schmidt K, Wagner C, et al. Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model. BMC Cancer. 2015 Feb 19;15:71. PubMed PMID: 25884642; PubMed Central PMCID: PMCPMC4340491. DOI:10.1186/s12885-015-1064-9
  • Lili LN, Matyunina LV, Walker LD,et al. Evidence for the importance of personalized molecular profiling in pancreatic cancer. Pancreas. 2014 Mar;43(2):198–211. PubMed PMID: 24518497; PubMed Central PMCID: PMCPMC4206352. DOI:10.1097/MPA.0000000000000020
  • Gutierrez ML, Sayagues JM, Abad Mdel M,et al. Cytogenetic heterogeneity of pancreatic ductal adenocarcinomas: identification of intratumoral pathways of clonal evolution. Histopathology. 2011 Feb;58(3):486–497. PubMed PMID: 21323969. DOI:10.1111/j.1365-2559.2011.03771.x
  • Mukherjee P, Ginardi AR, Madsen CS, et al. MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment. Glycoconj J. 2001 Nov-Dec;18(11–12):931–942. PubMed PMID: 12820727.
  • Mei L, Du W, Ma WW. Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises. J Gastrointest Oncol. 2016 Jun;7(3):487–494. DOI:10.21037/jgo.2016.03.03. PubMed PMID: 27284483; PubMed Central PMCID: PMCPMC4880763.
  • Di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013 Jun;144(6):1220–1229. DOI:10.1053/j.gastro.2013.01.071. PubMed PMID: 23622131; PubMed Central PMCID: PMCPMC3902845.
  • Chung V, McDonough S, Philip PA, et al. 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. 2016 Dec 15 PubMed PMID: 27978579. DOI:10.1001/jamaoncol.2016.5383.
  • Hancke S, Holm HH, Koch F. Ultrasonically guided percutaneous fine needle biopsy of the pancreas. Surg Gynecol Obstet. 1975 Mar;140(3):361–364. PubMed PMID: 1114427.
  • Livraghi T, Sangalli G, Giordano F, et al. Fine aspiration versus fine cutting needle, and comparison between smear cytology, inclusion cytology and microhistology in abdominal lesions. Tumori. 1988 Jun 30;74(3):361–364. PubMed PMID: 3041658.
  • Li L, Liu LZ, Wu QL,et al. CT-guided core needle biopsy in the diagnosis of pancreatic diseases with an automated biopsy gun. J Vasc Interv Radiol. 2008 Jan;19(1):89–94. PubMed PMID: 18192472. DOI:10.1016/j.jvir.2007.09.001
  • Lee YN, Moon JH, Kim HK,et al. Core biopsy needle versus standard aspiration needle for endoscopic ultrasound-guided sampling of solid pancreatic masses: a randomized parallel-group study. Endoscopy. 2014 Dec;46(12):1056–1062. PubMed PMID: 25098611. DOI:10.1055/s-0034-1377558
  • Bhutani M, Koduru P, Lanke G, et al. The emerging role of endoscopic ultrasound-guided core biopsy for the evaluation of solid pancreatic masses. Minerva Gastroenterol Dietol. 2015 Jun;61(2):51–59. PubMed PMID: 25675155.
  • Kalogeraki A, Papadakis GZ, Tamiolakis D,et al. EUS - fine- needle aspiration biopsy (FNAB) in the diagnosis of pancreatic adenocarcinoma: a review. Rom J Intern Med. 2016 Jan-Mar;54(1):24–30. PubMed PMID: 27141567. DOI:10.1515/rjim-2016-0002
  • Iglesias-Garcia J, Poley JW, Larghi A,et al. Feasibility and yield of a new EUS histology needle: results from a multicenter, pooled, cohort study. Gastrointest Endosc. 2011 Jun;73(6):1189–1196. PubMed PMID: 21420083. DOI:10.1016/j.gie.2011.01.053
  • Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004 Oct 15;10(20):6897–6904. PubMed PMID: 15501967. DOI:10.1158/1078-0432.CCR-04-0378
  • Hiraiwa K, Takeuchi H, Hasegawa H,et al. Clinical significance of circulating tumor cells in blood from patients with gastrointestinal cancers. Ann Surg Oncol. 2008 Nov;15(11):3092–3100. PubMed PMID: 18766405. DOI:10.1245/s10434-008-0122-9
  • Tjensvoll K, Nordgard O, Smaaland R. Circulating tumor cells in pancreatic cancer patients: methods of detection and clinical implications. Intl J Cancer. 2014 Jan 01;134(1):1–8. doi:10.1002/ijc.28134. PubMed PMID: 23447365.
  • Bidard FC, Huguet F, Louvet C,et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 2013 Aug;24(8):2057–2061. PubMed PMID: 23676420. DOI:10.1093/annonc/mdt176
  • Okubo K, Uenosono Y, Arigami T, et al. Clinical impact of circulating tumor cells and therapy response in pancreatic cancer. Eur J Surg Oncol. 2017 Feb 12 PubMed PMID: 28233633. DOI:10.1016/j.ejso.2017.01.241.
  • Takai E, Totoki Y, Nakamura H, et al. Clinical utility of circulating tumor DNA for molecular assessment and precision medicine in pancreatic cancer. Adv Exp Med Biol. 2016;924:13–17. PubMed PMID: 27753011. DOI:10.1007/978-3-319-42044-8_3
  • Sibinga Mulder BG, Mieog JS, Handgraaf HJ,et al. Targeted next-generation sequencing of FNA-derived DNA in pancreatic cancer. J Clin Pathol. 2017 Feb;70(2):174–178. PubMed PMID: 27672215. DOI:10.1136/jclinpath-2016-203928
  • Young G, Wang K, He J,et al. Clinical next-generation sequencing successfully applied to fine-needle aspirations of pulmonary and pancreatic neoplasms. Cancer Cytopathol. 2013 Dec;121(12):688–694. PubMed PMID: 23893923. DOI:10.1002/cncy.21338
  • Amato E, Molin MD, Mafficini A,et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014 Jul;233(3):217–227. PubMed PMID: 24604757; PubMed Central PMCID: PMCPMC4057302. DOI:10.1002/path.4344
  • Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016 Apr 21;2:16022. PubMed PMID: 27158978. DOI:10.1038/nrdp.2016.22
  • Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. Nature. 2015 Oct 15;526(7573):361–370. doi:10.1038/nature15819. PubMed PMID: 26469047.
  • Birnbaum DJ, Finetti P, Lopresti A, et al. A 25-gene classifier predicts overall survival in resectable pancreatic cancer. BMC Med. 2017 Sep 20;15(1):170. PubMed PMID: 28927421; PubMed Central PMCID: PMCPMC5606023. DOI:10.1186/s12916-017-0936-z
  • Creative Bioarray. Pancreatic tumor cells 2017 [cited 2017 Jun 3]. Available from: http://www.creative-bioarray.com/Products/Pancreatic-Tumor-Cells-list-106.htm
  • Masters JR. Human cancer cell lines: fact and fantasy. Nat Rev Mol Cell Biol. 2000 Dec;1(3):233–236. DOI:10.1038/35043102. PubMed PMID: 11252900; eng.
  • Zanoni M, Piccinini F, Arienti C, et al. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Rep. 2016 Jan 11;6:19103. PubMed PMID: 26752500; PubMed Central PMCID: PMCPMC4707510. DOI:10.1038/srep19103
  • Boj SF, Hwang CI, Baker LA,et al. Model organoids provide new research opportunities for ductal pancreatic cancer. Mol Cell Oncol. 2016 Jan;3(1):e1014757. PubMed PMID: 27308531; PubMed Central PMCID: PMCPMC4845167. eng. DOI:10.1080/23723556.2015.1014757
  • Boj SF, Hwang CI, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015 Jan 15;160(1–2):324–338. PubMed PMID: 25557080; PubMed Central PMCID: PMCPMC4334572. eng. DOI:10.1016/j.cell.2014.12.021
  • Logsdon CD, Arumugam T, Ramachandran V. Animal models of gastrointestinal and liver diseases. The difficulty of animal modeling of pancreatic cancer for preclinical evaluation of therapeutics. Am J Physiol Gastrointest Liver Physiol. 2015 Sep 01;309(5):G283–91. doi:10.1152/ajpgi.00169.2015. PubMed PMID: 26159697; PubMed Central PMCID: PMCPMC4556944. eng.
  • Hingorani SR, Wang L, Multani AS,et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005 May;7(5):469–483. PubMed PMID: 15894267. DOI:10.1016/j.ccr.2005.04.023
  • Rowley M, Ohashi A, Mondal G,et al. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology. 2011 Apr;140(4):1303-1313.e1-3. PubMed PMID: 21199651; PubMed Central PMCID: PMCPMC3066280. eng. DOI:10.1053/j.gastro.2010.12.039
  • Skoulidis F, Cassidy LD, Pisupati V, et al. Germline Brca2 heterozygosity promotes Kras(G12D)-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell. 2010 Nov 16;18(5):499–509. PubMed PMID: 21056012; eng. DOI:10.1016/j.ccr.2010.10.015
  • Tuveson DA, Zhu L, Gopinathan A, et al. Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Res. 2006 Jan 01;66(1):242–247. PubMed PMID: 16397237; eng. DOI:10.1158/0008-5472.can-05-2305
  • Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003 Dec 15;17(24):3112–3126. PubMed PMID: 14681207; PubMed Central PMCID: PMCPMC305262. eng. DOI:10.1101/gad.1158703
  • Bardeesy N, Cheng KH, Berger JH, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006 Nov 15;20(22):3130–3146. PubMed PMID: 17114584; PubMed Central PMCID: PMCPMC1635148. eng. DOI:10.1101/gad.1478706
  • Ijichi H, Chytil A, Gorska AE, et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev. 2006 Nov 15;20(22):3147–3160. PubMed PMID: 17114585; PubMed Central PMCID: PMCPMC1635149. eng. DOI:10.1101/gad.1475506
  • Ma L, Saiyin H. LSL-KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer. PubMed PMID: 28475592; PubMed Central PMCID: PMCPmc5419507. eng PloS One. 2017;125:e0176844. 10.1371/journal.pone.0176844
  • Mouse Tumor Biology Database. Pancreatic cancer patient derived xenograft 2017 [cited 2017 Jun 3]. Available from: http://tumor.informatics.jax.org/mtbwi/pdxSearchResults.do?primarySites=Pancreas&
  • Kawaguchi K, Igarashi K, Murakami T, et al. MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX). Oncotarget. 2017 May 07 PubMed PMID: 28537897; eng. DOI:10.18632/oncotarget.17667.
  • Hasgur S, Aryee KE, Shultz LD, et al. Generation of immunodeficient mice bearing human immune systems by the engraftment of hematopoietic stem cells. Meth Mol Biol. 2016;1438:67–78. PubMed PMID: 27150084; PubMed Central PMCID: PMCPMC5268072. eng. DOI:10.1007/978-1-4939-3661-8_4
  • Long J, Liu Z, Wu X,et al. Screening for genes and subnetworks associated with pancreatic cancer based on the gene expression profile. Mol Med Rep. 2016 May;13(5):3779–3786. PubMed PMID: 27035224; PubMed Central PMCID: PMCPMC4838159. DOI:10.3892/mmr.2016.5007
  • Long J, Liu Z, Wu X,et al. Gene expression profile analysis of pancreatic cancer based on microarray data. Mol Med Rep. 2016 May;13(5):3913–3919. PubMed PMID: 27035876; PubMed Central PMCID: PMCPMC4838162. DOI:10.3892/mmr.2016.5021
  • Jeon J, Nim S, Teyra J, et al. A systematic approach to identify novel cancer drug targets using machine learning, inhibitor design and high-throughput screening. Genome Med. 2014;6(7):57. PubMed PMID: 25165489; PubMed Central PMCID: PMCPMC4143549. DOI:10.1186/s13073-014-0057-7
  • Tempero MA, Berlin J, Ducreux M,et al. Pancreatic cancer treatment and research: an international expert panel discussion. Ann Oncol. 2011 Jul;22(7):1500–1506. PubMed PMID: 21199884. DOI:10.1093/annonc/mdq545
  • Dienstmann R, Rodon J, Tabernero J. Optimal design of trials to demonstrate the utility of genomically-guided therapy: putting Precision Cancer Medicine to the test. Mol Oncol. 2015 May;9(5):940–950. DOI:10.1016/j.molonc.2014.06.014. PubMed PMID: 25081646.
  • Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008 Aug 01;26(22):3785–3790. doi:10.1200/JCO.2008.16.0812. PubMed PMID: 18591545.
  • Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015 Oct;3(10):1148–1157. PubMed PMID: 26014098. DOI:10.1158/2326-6066.CIR-15-0059
  • Thompson D, Easton DF. Breast Cancer Linkage C. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002 Sep 18;94(18):1358–1365. PubMed PMID: 12237281.
  • Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002 Sep 18;94(18):1365–1372. PubMed PMID: 12237282.
  • Couch FJ, Johnson MR, Rabe KG,et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2007 Feb;16(2):342–346. PubMed PMID: 17301269.. DOI:10.1158/1055-9965.EPI-06-0783
  • Breast Cancer Linkage C. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999 Aug 04;91(15):1310–1316. PubMed PMID: 10433620.
  • Van Asperen CJ, Brohet RM, Meijers-Heijboer EJ,et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005 Sep;42(9):711–719. PubMed PMID: 16141007; PubMed Central PMCID: PMCPMC1736136. DOI:10.1136/jmg.2004.028829
  • Vyas O, Leung K, Ledbetter L,et al. Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation. Anticancer Drugs. 2015 Feb;26(2):224–226. PubMed PMID: 25304989. DOI:10.1097/CAD.0000000000000178
  • Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015 Feb 26;518(7540):495–501. PubMed PMID: 25719666; PubMed Central PMCID: PMCPMC4523082. DOI:10.1038/nature14169
  • Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014 Sep 09;111(6):1132–1138. PubMed PMID: 25072261; PubMed Central PMCID: PMCPMC4453851. DOI:10.1038/bjc.2014.418
  • Tran B, Moore S, Zogopoulos G, et al. Platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma (PC) associated with BRCA mutations: a translational case series. J Clin Oncol. 2012;30(4_suppl):217. PubMed PMID: 27983191. DOI:10.1200/jco.2012.30.4_suppl.217
  • Golan T, Sella T, O’Reilly EM, et al. Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. Br J Cancer. 2017 Mar 14;116(6):697–702. PubMed PMID: 28183138; PubMed Central PMCID: PMCPMC5355924. DOI:10.1038/bjc.2017.19
  • Haber JE. DNA recombination: the replication connection. Trends Biochem Sci. 1999 Jul;24(7):271–275. PubMed PMID: 10390616.
  • Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014 Jan;25(1):32–40. DOI:10.1093/annonc/mdt384. PubMed PMID: 24225019; PubMed Central PMCID: PMCPMC3868320.
  • Hay T, Matthews JR, Pietzka L, et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009 May 01;69(9):3850–3855. PubMed PMID: 19383921. DOI:10.1158/0008-5472.CAN-08-2388
  • Domchek SM, Hendifar AE, McWilliams RR, et al. RUCAPANC: an open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation. J Clin Oncol (Meeting Abstracts). 2016 January;34(suppl):abstr 4110.
  • Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004 Jul;4(7):528–539. DOI:10.1038/nrc1391. PubMed PMID: 15229478.
  • Knudson W, Biswas C, Toole BP. Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6767–6771. PubMed PMID: 6593727; PubMed Central PMCID: PMCPMC392012.
  • Sato N, Kohi S, Hirata K,et al. Role of hyaluronan in pancreatic cancer biology and therapy: once again in the spotlight. Cancer Sci. 2016 May;107(5):569–575. PubMed PMID: 26918382; PubMed Central PMCID: PMCPMC4970823. DOI:10.1111/cas.12913
  • Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 Mar 20;21(3):418–429. PubMed PMID: 22439937; PubMed Central PMCID: PMCPMC3371414. DOI:10.1016/j.ccr.2012.01.007
  • Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer. 2013 Jan 15;108(1):1–8. doi:10.1038/bjc.2012.569. PubMed PMID: 23299539; PubMed Central PMCID: PMCPMC3553539.
  • Misra S, Hascall VC, Markwald RR, et al. Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Front Immunol. 2015;6:201. PubMed PMID: 25999946; PubMed Central PMCID: PMCPMC4422082. DOI:10.3389/fimmu.2015.00201
  • Cheng XB, Kohi S, A K, et al. Hyaluronan stimulates pancreatic cancer cell motility. Oncotarget. 2016 Jan 26;7(4):4829–4840. PubMed PMID: 26684359; PubMed Central PMCID: PMCPMC4826246. DOI:10.18632/oncotarget.6617
  • Kultti A, Zhao C, Singha NC, et al. Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. Biomed Res Int. 2014;2014:817613. PubMed PMID: 25147816; PubMed Central PMCID: PMCPMC4131462. DOI:10.1155/2014/817613
  • Thompson CB, Shepard HM, O’Connor PM,et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther. 2010 Nov;9(11):3052–3064. PubMed PMID: 20978165. DOI:10.1158/1535-7163.MCT-10-0470
  • Jacobetz MA, Chan DS, Neesse A,et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013 Jan;62(1):112–120. PubMed PMID: 22466618; PubMed Central PMCID: PMCPMC3551211. DOI:10.1136/gutjnl-2012-302529
  • Singha NC, Nekoroski T, Zhao C,et al. Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy. Mol Cancer Ther. 2015 Feb;14(2):523–532. PubMed PMID: 25512619. DOI:10.1158/1535-7163.MCT-14-0580
  • Hingorani SR, Harris WP, Hendifar AE, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized phase II study. J Clin Oncol (Meeting Abstracts). 2015 January;33(Suppl):abstract4006.
  • Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509–2520. PubMed PMID: 26028255; PubMed Central PMCID: PMCPMC4481136. DOI:10.1056/NEJMoa1500596
  • Overman MJ, Lonardi S, Leone F, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: update from CheckMate 142. J Clin Oncol (Meeting Abstracts). 2017 January;35(suppl4s):abstr519.
  • Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. PubMed PMID: 28596308 Jun 08 2017. 10.1126/science.aan6733.
  • Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer. 2015;121(24):4382–4388.
  • Eatrides JM, Coppola D, Diffalha SA, et al. Microsatellite instability in pancreatic cancer. J Clin Oncol (Meeting Abstracts). 2016 June;34(suppl):abstre15753.
  • Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011 Feb;11(2):85–95. DOI:10.1038/nrc2981. PubMed PMID: 21258394.
  • Cohen R, Neuzillet C, Tijeras-Raballand A, et al. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget. 2015 Jul 10;6(19):16832–16847. PubMed PMID: 26164081; PubMed Central PMCID: PMCPMC4627277. DOI:10.18632/oncotarget.4160
  • Zhou W, Capello M, Fredolini C, et al. Proteomic analysis of pancreatic ductal adenocarcinoma cells reveals metabolic alterations. J Proteome Res. 2011 Apr 01;10(4):1944–1952. PubMed PMID: 21309613. DOI:10.1021/pr101179t
  • Vander Heiden MG, Plas DR, Rathmell JC, et al. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol. 2001 Sep;21(17):5899–5912. PubMed PMID: 11486029; PubMed Central PMCID: PMCPMC87309.
  • Alistar A, Morris BB, Desnoyer R,et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017 Jun;18(6):770–778. PubMed PMID: 28495639. DOI:10.1016/S1470-2045(17)30314-5
  • Hassan R, Laszik ZG, Lerner M, et al. Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 2005 Dec;124(6):838–845. PubMed PMID: 16416732.
  • Argani P, Iacobuzio-Donahue C, Ryu B et al. 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 Dec 7 (12): 3862–3868. PubMed PMID: 11751476.
  • Rump A, Morikawa Y, Tanaka M, et al. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem. 2004 Mar 05;279(10):9190–9198. PubMed PMID: 14676194.
  • Chen SH, Hung WC, Wang P, et al. Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci Rep. 2013;3:1870. PubMed PMID: 23694968; PubMed Central PMCID: PMCPMC3660778. DOI:10.1038/srep01870
  • Li M, Bharadwaj U, Zhang R,et al. Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. Mol Cancer Ther. 2008 Feb;7(2):286–296. PubMed PMID: 18281514; PubMed Central PMCID: PMCPMC2929838. DOI:10.1158/1535-7163.MCT-07-0483
  • Bharadwaj U, Marin-Muller C, Li M,et al. Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis. 2011 Jul;32(7):1013–1024. PubMed PMID: 21515913; PubMed Central PMCID: PMCPMC3128561. DOI:10.1093/carcin/bgr075
  • Bharadwaj U, Li M, Chen C,et al. Mesothelin-induced pancreatic cancer cell proliferation involves alteration of cyclin E via activation of signal transducer and activator of transcription protein 3. Mol Cancer Res. 2008 Nov;6(11):1755–1765. PubMed PMID: 19010822; PubMed Central PMCID: PMCPMC2929833. DOI:10.1158/1541-7786.MCR-08-0095
  • Chang MC, Chen CA, Hsieh CY, et al. Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 2009 Dec 10;424(3):449–458. PubMed PMID: 19747165. DOI:10.1042/BJ20082196
  • Cheng WF, Huang CY, Chang MC, et al. High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. Br J Cancer. 2009 Apr 07;100(7):1144–1153. PubMed PMID: 19293794; PubMed Central PMCID: PMCPMC2669998. DOI:10.1038/sj.bjc.6604964
  • Chowdhury PS, Viner JL, Beers R, et al. Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):669–674. PubMed PMID: 9435250; PubMed Central PMCID: PMCPMC18478.
  • Chowdhury PS, Pastan I. Improving antibody affinity by mimicking somatic hypermutation in vitro. Nat Biotechnol. 1999 Jun;17(6):568–572. DOI:10.1038/9872. PubMed PMID: 10385321.
  • Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 Sep 01;13(17):5144–5149. PubMed PMID: 17785569. DOI:10.1158/1078-0432.CCR-07-0869
  • Uchida T, Muramoto M, Kyunou H, et al. Clinical outcome of high-intensity focused ultrasound for treating benign prostatic hyperplasia: preliminary report. Urology. 1998 Jul;52(1):66–71. PubMed PMID: 9671873.
  • Hassan R, Cohen SJ, Phillips M, et al. Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res. 2010 Dec 15;16(24):6132–6138. PubMed PMID: 21037025; PubMed Central PMCID: PMCPMC3057907. DOI:10.1158/1078-0432.CCR-10-2275
  • Fujisaka Y, Kurata T, Tanaka K,et al. Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors. Invest New Drugs. 2015 Apr;33(2):380–388. PubMed PMID: 25502863; PubMed Central PMCID: PMCPMC4387254. DOI:10.1007/s10637-014-0196-0
  • Brockstedt DG, Giedlin MA, Leong ML, et al. Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13832–13837. PubMed PMID: 15365184; PubMed Central PMCID: PMCPMC518841. DOI:10.1073/pnas.0406035101
  • Le DT, Ko AH, Wainberg ZA, et al. Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE study). J Clin Oncol (Meeting Abstracts). 2017 January 20;35(Suppl4S):abstract345.
  • Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. PubMed PMID: 11597398. Eur J Cancer. 2001 Sep;37 Suppl 4:S3–8
  • Perez-Soler R. HER1/EGFR targeting: refining the strategy. Oncologist. 2004;9(1): 58–67. PubMed PMID: 14755015.
  • Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960–1966. PubMed PMID: 17452677; eng. DOI:10.1200/jco.2006.07.9525
  • Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 2004;22(5):706–712. PubMed PMID: 15581051.
  • Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010 Aug 01;28(22):3605–3610. PubMed PMID: 20606093; PubMed Central PMCID: PMCPMC2917315. DOI:10.1200/JCO.2009.25.7550
  • Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012 Mar 13;106(6):1033–1038. PubMed PMID: 22374460; PubMed Central PMCID: PMCPMC3304403. DOI:10.1038/bjc.2012.18
  • Safran H, Miner T, Bahary N, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol. 2011 Feb;34(1):50–52. PubMed PMID: 24757739.
  • Maron R, Schechter B, Mancini M, et al. Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15389–15394. PubMed PMID: 24003140; PubMed Central PMCID: PMCPMC3780883. DOI:10.1073/pnas.1313857110
  • Assenat E, Mineur L, Mollevi C, et al. Phase II study evaluating the association of gemcitabine, trastuzumab, and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1). J Clin Oncol (Meeting Abstracts). 2015 January;33(suppl 3):abstr 379.
  • Assenat E, Azria D, Mollevi C, et al. Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the “THERAPY” phase 1-2 trial. Oncotarget. 2015 May 20;6(14):12796–12808. PubMed PMID: 25918250; PubMed Central PMCID: PMCPMC4494975. DOI:10.18632/oncotarget.3473
  • Perez SA, Sotiropoulou PA, Sotiriadou NN,et al. HER-2/neu-derived peptide 884-899 is expressed by human breast, colorectal and pancreatic adenocarcinomas and is recognized by in-vitro-induced specific CD4(+) T cell clones. Cancer Immunol Immunother. 2002 Jan;50(11):615–624. PubMed PMID: 11807625. DOI:10.1007/s002620100225
  • Sotiriadou R, Perez SA, Gritzapis AD, et al. Peptide HER2(776-788) represents a naturally processed broad MHC class II-restricted T cell epitope. Br J Cancer. 2001 Nov 16;85(10):1527–1534. PubMed PMID: 11720440; PubMed Central PMCID: PMCPMC2363935. DOI:10.1054/bjoc.2001.2089
  • Zhou X, Li J, Wang Z, et al. Cellular immunotherapy for carcinoma using genetically modified EGFR-specific T lymphocytes. Neoplasia (New York, NY). 2013 May;15(5):544–553. PubMed PMID: 23633926; PubMed Central PMCID: PMCPMC3638357.
  • Cragg GM, Grothaus PG, Newman DJ. Impact of natural products on developing new anti-cancer agents. Chem Rev. 2009 Jul;109(7):3012–3043. DOI:10.1021/cr900019j. PubMed PMID: 19422222.
  • Yue Q, Gao G, Zou G, et al. Natural products as adjunctive treatment for pancreatic cancer: recent trends and advancements. Biomed Res Int. 2017;2017:8412508. PubMed PMID: 28232946; PubMed Central PMCID: PMCPMC5292383 authors declared no potential conflict of interests with respect to the research, authorship, and/or publication of this article. DOI:10.1155/2017/8412508
  • Fairman D, Narwal R, Liang M, et al. Pharmacokinetics of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts). 2014 May 20;32(15_suppl):2602.
  • Lee FY, Borzilleri R, Fairchild CR, et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res. 2001 May;7(5):1429–1437. PubMed PMID: 11350914.
  • Phillips PA, Dudeja V, McCarroll JA, et al. Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res. 2007 Oct 1;67(19):9407–9416. PubMed PMID: 17909050. DOI:10.1158/0008-5472.CAN-07-1077
  • Chugh R, Sangwan V, Patil SP, et al. A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer. Sci Transl Med. 2012 Oct 17;4(156):156ra139. PubMed PMID: 23076356; PubMed Central PMCID: PMCPMC3656604. DOI:10.1126/scitranslmed.3004334
  • Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.
  • Wang-Gillam A, Li C-P, Bodoky G, et al. Updated overall survival analysis of NAPOLI-1: phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. ASCO Meet Abstr. 2016 January 30;34(4_suppl):417.
  • Ando Y, Saka H, Ando M, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 2000 Dec 15;60(24):6921–6926. PubMed PMID: 11156391.
  • Marcuello E, Altes A, Menoyo A, et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004 Aug 16;91(4):678–682. PubMed PMID: 15280927; PubMed Central PMCID: PMCPMC2364770. DOI:10.1038/sj.bjc.6602042
  • Saif MW, Lee Y, Kim R. Harnessing gemcitabine metabolism: a step towards personalized medicine for pancreatic cancer. Ther Adv Med Oncol. 2012 Nov;4(6):341–346. DOI:10.1177/1758834012453755. PubMed PMID: 23118809; PubMed Central PMCID: PMCPMC3481558.
  • Young JD, Yao SY, Sun L,et al. Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica. 2008 Jul;38(7–8):995–1021. PubMed PMID: 18668437. DOI:10.1080/00498250801927427
  • Garcia-Manteiga J, Molina-Arcas M, Casado FJ, et al. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2’,2’-difluorodeoxycytidine- induced cytotoxicity. Clin Cancer Res. 2003 Oct 15;9(13):5000–5008. PubMed PMID: 14581375.
  • Spratlin J, Sangha R, Glubrecht D, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004 Oct 15;10(20):6956–6961. PubMed PMID: 15501974. DOI:10.1158/1078-0432.CCR-04-0224
  • Morinaga S, Nakamura Y, Watanabe T, et al. Immunohistochemical analysis of human equilibrative nucleoside transporter-1 (hENT1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy. Ann Surg Oncol. 2012 Jul;19 Suppl 3:S558–64. PubMed PMID: 21913012. DOI:10.1245/s10434-011-2054-z
  • Marechal R, Bachet JB, Mackey JR,et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology. 2012 Sep;143(3):664-74e1-6. PubMed PMID: 22705007. DOI:10.1053/j.gastro.2012.06.006
  • Farrell JJ, Elsaleh H, Garcia M,et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009 Jan;136(1):187–195. PubMed PMID: 18992248. DOI:10.1053/j.gastro.2008.09.067
  • Greenhalf W, Ghaneh P, Neoptolemos JP,et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst. 2014 Jan;106(1):djt347. PubMed PMID: 24301456. DOI:10.1093/jnci/djt347
  • Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006 Apr 01;66(7):3928–3935. PubMed PMID: 16585222. DOI:10.1158/0008-5472.CAN-05-4203
  • Sinn M, Riess H, Sinn BV,et al. Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial. Eur J Cancer. 2015 Aug;51(12):1546–1554. PubMed PMID: 26049689. DOI:10.1016/j.ejca.2015.05.005
  • Svrcek M, Cros J, Marechal R,et al. Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies. Histopathology. 2015 Feb;66(3):457–462. PubMed PMID: 25298108. DOI:10.1111/his.12577
  • Kojima K, Vickers SM, Adsay NV, et al. Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 2007 Sep 01;67(17):8121–8130. PubMed PMID: 17804724. DOI:10.1158/0008-5472.CAN-06-4167
  • Schwarte-Waldhoff I, Volpert OV, Bouck NP, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9624–9629. PubMed PMID: 10944227; PubMed Central PMCID: PMCPMC16915.
  • Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009 Apr 10;27(11):1806–1813. PubMed PMID: 19273710; PubMed Central PMCID: PMCPMC2668706. DOI:10.1200/JCO.2008.17.7188
  • Crane CH, Varadhachary GR, Yordy JS, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol. 2011 Aug 01;29(22):3037–3043. PubMed PMID: 21709185; PubMed Central PMCID: PMCPMC3157965. DOI:10.1200/JCO.2010.33.8038
  • Whittle MC, Izeradjene K, Rani PG, et al. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell. 2015 Jun 04;161(6):1345–1360. PubMed PMID: 26004068; PubMed Central PMCID: PMCPMC4458240. DOI:10.1016/j.cell.2015.04.048
  • Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009 Oct;10(10):704–714. DOI:10.1038/nrg2634. PubMed PMID: 19763153; PubMed Central PMCID: PMCPMC3467096.
  • Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006 Apr 6;(4):259–269. PubMed PMID: 16557279. Doi:10.1038/nrc1840
  • Lee EJ, Gusev Y, Jiang J, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007 Mar 01;120(5):1046–1054. PubMed PMID: 17149698; PubMed Central PMCID: PMCPMC2680248. DOI:10.1002/ijc.22394
  • Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. Jama. 2007 May 02;297(17):1901–1908. PubMed PMID: 17473300. DOI:10.1001/jama.297.17.1901
  • Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257–2261. PubMed PMID: 16461460; PubMed Central PMCID: PMCPMC1413718. DOI:10.1073/pnas.0510565103
  • Bryant JL, Britson J, Balko JM, et al. A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT. Br J Cancer. 2012 Jan 03;106(1):148–156. PubMed PMID: 22045191; PubMed Central PMCID: PMCPMC3251842. DOI:10.1038/bjc.2011.465
  • Garajova I, Le LTY, Giovannetti E, et al. The role of microRNAs in resistance to current pancreatic cancer treatment: translational studies and basic protocols for extraction and PCR analysis. Methods Mol Biol. 2016;1395:163–187. PubMed PMID: 26910074. DOI:10.1007/978-1-4939-3347-1_10
  • Hoadley KA, Yau C, Wolf DM, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014 Aug 14;158(4):929–944. PubMed PMID: 25109877; PubMed Central PMCID: PMCPMC4152462. DOI:10.1016/j.cell.2014.06.049
  • Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17(4):500–503.
  • Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nature Genetics. 2015;47(10):1168–1178. DOI:10.1038/ng.3398.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.