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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2015

Open Access 01-12-2015 | Review

Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future

Authors: Gaurav Goel, Weijing Sun

Published in: Journal of Hematology & Oncology | Issue 1/2015

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Abstract

Despite a few breakthroughs in therapy for advanced disease in the recent years, pancreatic ductal adenocarcinoma continues to remain one of the most challenging human malignancies to treat. The overall prognosis for the majority of patients with pancreatic cancer is rather dismal, and therefore, more effective treatment options are being desperately sought. The practical goals of management are to improve the cure rates for patients with resectable disease, achieve a higher conversion rate of locally advanced tumor into potentially resectable disease, and finally, prolong the overall survival for those who develop metastatic disease. Our understanding of the complex genetic alterations, the implicated molecular pathways, and the role of desmoplastic stroma in pancreatic cancer tumorigenesis has increased several folds in the recent years. This has facilitated the development of novel therapeutic strategies against pancreatic cancer, some of which are currently under evaluation in ongoing preclinical and clinical studies. This review will summarize the existing treatment approaches for this devastating disease and also discuss the promising therapeutic approaches that are currently in different stages of clinical development.
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.PubMed
2.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.PubMedCentralPubMed
3.
Blackford A, Parmigiani G, Kensler TW, Wolfgang C, Jones S, Zhang X, et al. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 2009;69:3681–8.PubMedCentralPubMed
4.
Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, et al. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev. 2009;18:765–76.PubMedCentralPubMed
5.
Philip B, Roland CL, Daniluk J, Liu Y, Chatterjee D, Gomez SB, et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2013;145:1449–58.PubMed
6.
Amaral AF, Porta M, Silverman DT, Milne RL, Kogevinas M, Rothman N, et al. Pancreatic cancer risk and levels of trace elements. Gut. 2012;61:1583–8.PubMedCentralPubMed
7.
8.
Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med. 2009;133:365–74.PubMed
9.
Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update on familial pancreatic cancer. Adv Surg. 2010;44:293–311.PubMedCentralPubMed
10.
Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013;62:339–47.PubMedCentralPubMed
11.
Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–72.PubMed
12.
13.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–7.PubMedCentralPubMed
14.
15.
Caldas C, Kern SE. K-ras mutation and pancreatic adenocarcinoma. Int J Pancreatol. 1995;18:1–6.PubMed
16.
di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144:1220–9.PubMedCentralPubMed
17.
Yachida S, Iacobuzio-Donahue CA. Evolution and dynamics of pancreatic cancer progression. Oncogene. 2013;32:5253–60.PubMed
18.
Agbunag C, Bar-Sagi D. Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells. Cancer Res. 2004;64:5659–63.PubMed
19.
Sasaki S, Yamamoto H, Kaneto H, Ozeki I, Adachi Y, Takagi H, et al. Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas. Oncol Rep. 2003;10:21–5.PubMed
20.
Yachida S, Iacobuzio-Donahue CA. The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med. 2009;133:413–22.PubMed
21.
Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.PubMed
22.
Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A. 2009;106:4254–9.PubMedCentralPubMed
23.
Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91:586–94.PubMed
24.
25.
Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–81.PubMed
26.
Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10.PubMed
27.
Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011;18:1319–26.PubMedCentralPubMed
28.
Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77.PubMed
29.
Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–26.PubMed
30.
Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335–9.PubMed
31.
Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998;16:3843–50.PubMed
32.
Pisters PW, Wolff RA, Janjan NA, Cleary KR, Charnsangavej C, Crane CN, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol. 2002;20:2537–44.PubMed
33.
Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496–502.PubMed
34.
Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3487–95.PubMed
35.
Paulson AS, Tran Cao HS, Tempero MA, Lowy AM. Therapeutic advances in pancreatic cancer. Gastroenterology. 2013;144:1316–26.PubMed
36.
Mehta VK, Fisher G, Ford JA, Poen JC, Vierra MA, Oberhelman H, et al. Preoperative chemoradiation for marginally resectable adenocarcinoma of the pancreas. J Gastrointest Surg. 2001;5:27–35.PubMed
37.
Small Jr W, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008;26:942–7.PubMed
38.
Stokes JB, Nolan NJ, Stelow EB, Walters DM, Weiss GR, de Lange EE, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol. 2011;18:619–27.PubMed
39.
Patel M, Hoffe S, Malafa M, Hodul P, Klapman J, Centeno B, et al. Neoadjuvant GTX chemotherapy and IMRT-based chemoradiation for borderline resectable pancreatic cancer. J Surg Oncol. 2011;104:155–61.PubMedCentralPubMed
40.
Moertel CG, Frytak S, Hahn RG, O’Connell MJ, Reitemeier RJ, Rubin J, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981;48:1705–10.PubMed
41.
Loehrer Sr PJ, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29:4105–12.PubMedCentralPubMed
42.
Li CP, Chao Y, Chi KH, Chan WK, Teng HC, Lee RC, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol, Biol, Phys. 2003;57:98–104.
43.
Rocha Lima CM, Green MR, Rotche R, Miller Jr WH, Jeffrey GM, Cisar LA, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22:3776–83.PubMed
44.
Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22:1430–8.PubMed
45.
Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–16.PubMed
46.
Ghosn M, Farhat F, Kattan J, Younes F, Moukadem W, Nasr F, et al. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. Am J Clin Oncol. 2007;30:15–20.PubMed
47.
Boone BA, Steve J, Krasinskas AM, Zureikat AH, Lembersky BC, Gibson MK, et al. Outcomes with FOLFIRINOX for borderline resectable and locally unresectable pancreatic cancer. J Surg Oncol. 2013;108:236–41.PubMed
48.
Faris JE, Blaszkowsky LS, McDermott S, Guimaraes AR, Szymonifka J, Huynh MA, et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. Oncologist. 2013;18:543–8.PubMedCentralPubMed
49.
Gunturu KS, Yao X, Cong X, Thumar JR, Hochster HS, Stein SM, et al. FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity. Med Oncol. 2013;30:361.PubMed
50.
Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012;12:199.PubMedCentralPubMed
51.
Huguet F, Andre T, Hammel P, Artru P, Balosso J, Selle F, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;25:326–31.PubMed
52.
Krishnan S, Rana V, Janjan NA, Varadhachary GR, Abbruzzese JL, Das P, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 2007;110:47–55.PubMed
53.
Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.PubMed
54.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.PubMed
55.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.PubMed
56.
Mahaseth H, Kauh JS, Brutcher E, Hawk NN, Kim S, Chen Z. Safety and efficacy of modified FOLFIRINOX in pancreatic cancer: a retrospective experience. In: ASCO Meeting. 2012.
57.
Edmonds C, Cengel KA. Tumor-stroma interactions in pancreatic cancer: Will this SPARC prove a raging fire? Cancer Biol Ther. 2008;7:1816–7.PubMed
58.
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548–54.
59.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.
60.
Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol. 1999;17:3631–52.PubMed
61.
Cohen SJ, Ho L, Ranganathan S, Abbruzzese JL, Alpaugh RK, Beard M, et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol. 2003;21:1301–6.PubMed
62.
Macdonald JS, McCoy S, Whitehead RP, Iqbal S, Wade 3rd JL, Giguere JK, et al. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs. 2005;23:485–7.PubMed
63.
Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.PubMedCentralPubMed
64.
Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30:1216–23.PubMed
65.
Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50:2072–81.PubMed
66.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011;25:460–70.PubMedCentralPubMed
67.
Lemoine NR, Hughes CM, Barton CM, Poulsom R, Jeffery RE, Kloppel G, et al. The epidermal growth factor receptor in human pancreatic cancer. J Pathol. 1992;166:7–12.PubMed
68.
Safran H, Steinhoff M, Mangray S, Rathore R, King TC, Chai L, et al. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol. 2001;24:496–9.PubMed
69.
Kulke MH, Blaszkowsky LS, Ryan DP, Clark JW, Meyerhardt JA, Zhu AX, et al. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol. 2007;25:4787–92.PubMed
70.
Xiong HQ, Rosenberg A, LoBuglio A, Schmidt W, Wolff RA, Deutsch J, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2004;22:2610–6.PubMed
71.
Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28:3605–10.PubMedCentralPubMed
72.
Kim GP, Foster NR, Salim M, Flynn PJ, Moore DF, Zon R, et al. Randomized phase II trial of panitumumab, erlotinib, and gemcitabine (PGE) versus erlotinib-gemcitabine (GE) in patients with untreated, metastatic pancreatic adenocarcinoma. J Clin Oncol. 2011;29(suppl):abstr 4030.
73.
Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 2004;22:706–12.PubMed
74.
75.
Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22.PubMedCentralPubMed
76.
Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27:2231–7.PubMed
77.
Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008;371:2101–8.PubMed
78.
Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12:256–62.PubMed
79.
Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013;49:2633–42.PubMed
80.
Goncalves A, Gilabert M, Francois E, Dahan L, Perrier H, Lamy R, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23:2799–805.PubMed
81.
Deplanque G, Demarchi M, Hebbar M, Flynn PJ, Melichar B, Atkins J, et al. Masitinib in nonresectable pancreatic cancer: results of a phase III randomized placebo-controlled trial. J Clin Oncol. 2013;31(suppl):abstr 158.
82.
Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson Jr JJ, Rocha-Lima CM, et al. 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;23:2834–42.PubMed
83.
Philip PA, Goldman BH, Ramanathan RK, Lenz H, Lowy AM, Philip PA, et al. Phase I randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib as first-line treatment in patients with metastatic pancreatic cancer (SWOG-0727). J Clin Oncol. 2012;30 suppl 4:abstr 198.
84.
Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol. 2013;6:88.PubMedCentralPubMed
85.
Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–8.PubMedCentralPubMed
86.
Cui J, Jiang W, Wang S, Wang L, Xie K. Role of Wnt/β-catenin signaling in drug resistance of pancreatic cancer. Curr Pharm Des. 2012;18:2464–71.PubMed
87.
Farhana L, Dawson MI, Das JK, Murshed F, Xia Z, Hadden TJ, et al. Adamantyl retinoid-related molecules induce apoptosis in pancreatic cancer cells by inhibiting IGF-1R and Wnt/β-catenin pathways. J Oncol. 2012;2012:796729.PubMedCentralPubMed
88.
Sjolund J, Manetopoulos C, Stockhausen MT, Axelson H. The Notch pathway in cancer: differentiation gone awry. Eur J C ancer. 2005;41:2620–9.
89.
Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87.PubMedCentralPubMed
90.
Mizuma M, Rasheed ZA, Yabuuchi S, Omura N, Campbell NR, de Wilde RF, et al. The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. Mol Cancer Ther. 2012;11:1999–2009.PubMedCentralPubMed
91.
Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007;104:5103–8.PubMedCentralPubMed
92.
Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.PubMedCentralPubMed
93.
Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, et al. A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer. J Clin Oncol. 2013;31(suppl):abstr 4010.
94.
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;87:161–7.PubMedCentralPubMed
95.
Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, et al. 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;21:3296–302.PubMed
96.
Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J, Jr., Chiorean EG, Rosen PJ, et al.: Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2014.
97.
Fuxe J, Karlsson MC. TGF-β-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol. 2012;22:455–61.PubMed
98.
Oettle H, Seufferlein T, Luger T, Schmid RM, Wichert GV, Endlicher E, et al. Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. J Clin Oncol. 2012;30(suppl):abstr 4034.
99.
Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009;69:6539–45.PubMedCentralPubMed
100.
Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–8.PubMedCentralPubMed
101.
Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;18:2905–12.PubMedCentralPubMed
102.
Hwang AL, Haynes K, Hwang WT, Yang YX. Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas. 2013;42:1054–9.PubMedCentralPubMed
103.
Lu Y, Bellgrau D, Dwyer-Nield LD, Malkinson AM, Duke RC, Rodell TC, et al. Mutation-selective tumor remission with Ras-targeted, whole yeast-based immunotherapy. Cancer Res. 2004;64:5084–8.PubMed
104.
Strong JE, Coffey MC, Tang D, Sabinin P, Lee PW. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 1998;17:3351–62.PubMedCentralPubMed
105.
Morse MA, Nair SK, Boczkowski D, Tyler D, Hurwitz HI, Proia A, et al. 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.PubMed
106.
Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, et al. 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;54:254–64.PubMed
107.
Rong Y, Qin X, Jin D, Lou W, Wu L, Wang D, et al. A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer. Clin Exp Med. 2012;12:173–80.PubMed
108.
Maki RG, Livingston PO, Lewis JJ, Janetzki S, Klimstra D, Desantis D, et al. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci. 2007;52:1964–72.PubMed
109.
Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013;17:94–100. discussion p 100–101.PubMed
110.
Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer. 2006;95:1474–82.PubMedCentralPubMed
111.
Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012;41:374–9.PubMed
112.
Wolpin BM, O’Reilly EM, Ko YJ, Blaszkowsky LS, Rarick M, Rocha-Lima CM, et al. Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. Ann Oncol. 2013;24:1792–801.PubMedCentralPubMed
113.
Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.PubMedCentralPubMed
114.
Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.PubMed
115.
Ocean AJ, Pennington KL, Guarino MJ, Sheikh A, Bekaii-Saab T, Serafini AN, et al. Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. Cancer. 2012;118:5497–506.PubMedCentralPubMed
116.
Chmielewski M, Hahn O, Rappl G, Nowak M, Schmidt-Wolf IH, Hombach AA, et al. T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice. Gastroenterology. 2012;143:1095–107.PubMed
117.
Ko AH, Tempero MA, Shan Y, Su W, Lin Y, Dito E, et al. A multinational phase II study of PEP02 (liposome irinotecan) for patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2011;29(suppl):abstr 4069.
118.
Ozaka M, Matsumura Y, Ishii H, Omuro Y, Itoi T, Mouri H, et al. Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol. 2012;69:1197–204.PubMed
119.
Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, et al. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01). Jpn J Clin Oncol. 2008;38:227–9.PubMed
120.
Fukutomi A, Uesaka K, Boku N, Kanemoto H, Konishi M, Matsumoto I, et al. JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer. J Clin Oncol. 2013;31(suppl):abstr 4008.
121.
Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66:3928–35.PubMed
122.
Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, et al. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 2013;31:4453–61.PubMed
123.
Xie H, Jiang W, Jiang J, Wang Y, Kim R, Liu X, et al. Predictive and prognostic roles of ribonucleotide reductase M1 in resectable pancreatic adenocarcinoma. Cancer. 2013;119:173–81.PubMed
124.
Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M, et al. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer. 2007;96:457–63.PubMedCentralPubMed
125.
Lambrechts D, Claes B, Delmar P, Reumers J, Mazzone M, Yesilyurt BT, et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol. 2012;13:724–33.PubMed
126.
Yu KH, Ricigliano M, Hidalgo M, Abou-Alfa GK, Lowery MA, Saltz LB, et al. Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer. Clin Cancer Res. 2014;20:5281–9.PubMed
Metadata
Title
Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future
Authors
Gaurav Goel
Weijing Sun
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-015-0141-5

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