Therapeutic Targets of Pancreatic Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 YUWen , XUEWu-song , MENSi-ye ,  XUXiu-qin , LIUBao-qing , CHENZi-yan , ANJia-lin , YANGCheng-cheng

Department of General Surgery, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China;

Corresponding author：

XUXiu-qin, Email: xuxiuqingg@sina.com

Keywords：

Pancreatic cancer; Therapeutic targets; Signal-transduction pathways; Immune response; Stroma reaction; Epigenetic changes

DOI：

10.7507/1007-9424.20150099

Video：

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Objective To summarize the therapeutic targets of pancreatic cancer (PC). Methods The related literatures about the therapeutic targets of PC were reviewed. Results PC was one of the most challenging tumor in worldwide, and was characterized as a highly aggressive disease with poor overall prognosis and a high mortality rate. The hallmark of PC was its poor response to radio-and chemo-therapy. Current chemotherapeutic regimens could not provide substantial survival benefit with a clear increase in overall survival. Recently, several new approaches which could significantly improve the clinical outcome of PC had been described, involving signal-transduction pathways, immune response, stroma reaction, and epigenetic changes. Conclusions Many therapeutic targets are involved in the treatment of PC. As current therapies failed to significantly improve the progression and the survival of PC, new therapeutic approaches and clinical studies are strongly required.

Citation： YUWen, XUEWu-song, MENSi-ye, XUXiu-qin, LIUBao-qing, CHENZi-yan, ANJia-lin, YANGCheng-cheng. Therapeutic Targets of Pancreatic Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(3): 369-373. doi: 10.7507/1007-9424.20150099 Copy

1.	Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2013. Ann Oncol, 2013, 24(3):792-800.
2.	Ni X, Yang J, Li M. Imaging-guided curative surgical resection of pancreatic cancer in a xenograft mouse model. Cancer Lett, 2012, 324(2):179-185.
3.	Michl P, Gress TM. Current concepts and novel targets in advanced pancreatic cancer. Gut, 2013, 62(2):317-326.
4.	Remmers N, Bailey JM, Mohr AM, et al. Molecular pathology of early pancreatic cancer. Cancer Biomark, 2010, 9(1-6):421-440.
5.	Wedén S, Klemp M, Gladhaug IP, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer, 2011, 128(5):1120-1128.
6.	Deangelo DJ, Neuberg D, Amrein PC, et al. A phase Ⅱ study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia. Leuk Res, 2014, 38(4):430-434.
7.	Troiani T, Martinelli E, Capasso A, et al. Targeting EGFR in pancre-atic cancer treatment. Curr Drug Targets, 2012, 13(6):802-810.
8.	Vaccaro V, Bria E, Sperduti I, et al. First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer. World J Gastroenterol, 2013, 19(28):4511-4519.
9.	Gonçalves A, Gilabert M, François E, et al. BAYPAN study:a double-blind phase Ⅲ randomized trial comparing gemcitabine plus sora-fenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol, 2012, 23(11):2799-2805.
10.	Ucar DA, Magis AT, He DH, et al. Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo. Anticancer Agents Med Chem, 2013, 13(4):595-602.
11.	Prasad R, Vaid M, Katiyar SK. Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway. PLoS One, 2012, 7(8):e43064.
12.	Li J, Liang X, Yang X. Ursolic acid inhibits growth and induces apop-tosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways. Oncol Rep, 2012, 28(2):501-510.
13.	Zhang Y, Zhang J, Xu K, et al. PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immunoresistance in pancreatic cancer. Hepatogastroenterology, 2013, 60(127):1766-1772.
14.	Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 2013, 23(3):406-420.
15.	Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol, 2009, 27(2):193-198.
16.	Deeb D, Gao X, Liu YB, et al. Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-κB/mTOR signaling proteins and anti-apoptotic Bcl-2. Int J Oncol, 2014, 44(5):1707-1715.
17.	Pollak M. Metformin and pancreatic cancer:a clue requiring investigation. Clin Cancer Res, 2012, 18(10):2723-2725.
18.	Bodmer M, Becker C, Meier C, et al. Use of antidiabetic agents and the risk of pancreatic cancer:a case-control analysis. Am J Gastroenterol, 2012, 107(4):620-626.
19.	Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcrip-tional activation in response to IFNs and other extracellular signa-ling proteins. Science, 1994, 264(5164):1415-1421.
20.	Panni RZ, Sanford DE, Belt BA, et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother, 2014, 63(5):513-528.
21.	Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell, 2011, 19(4):456-469.
22.	Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res, 2011, 71(14):5020-5029.
23.	Porcelli L, Quatrale AE, Mantuano P, et al. Optimize radiochemo-therapy in pancreatic cancer:PARP inhibitors a new therapeutic opportunity. Mol Oncol, 2013, 7(3):308-322.
24.	Yuan K, Sun Y, Zhou T, et al. PARP-1 regulates resistance of pancreatic cancer to TRAIL therapy. Clin Cancer Res, 2013, 19(17):4750-4759.
25.	Sawai H, Okada Y, Kazanjian K, et al. The G691S RET polymorp-hism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res, 2005, 65(24):11536-11544.
26.	Cavel O, Shomron O, Shabtay A, et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res, 2012, 72(22):5733-5743.
27.	Liu H, Ma Q, Li J. High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem, 2011, 347(1-2):95-101.
28.	Gil Z, Cavel O, Kelly K, et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst, 2010, 102(2):107-118.
29.	Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4):252-264.
30.	Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer, 2012, 12(4):237-251.
31.	Koido S, Homma S, Takahara A, et al. Current immunotherapeutic approaches in pancreatic cancer. Clin Dev Immunol, 2011, 2011:267539.
32.	Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother, 2013, 36(7):382-389.
33.	Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science, 2011, 331(6024):1612-1616.
34.	Vonderheide RH, Bajor DL, Winograd R, et al. CD40 immunoth-erapy for pancreatic cancer. Cancer Immunol Immunother, 2013, 62(5):949-954.
35.	Bubenik J, Den Otter W, Huland E. Local cytokine therapy of cancer:interleukin-2, interferons and related cytokines. Cancer Immunol Immunother, 2000, 49(2):116-122.
36.	Wagner K, Schulz P, Scholz A, et al. The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clin Cancer Res, 2008, 14(15):4951-4960.
37.	Michl P, Gress TM. Improving drug delivery to pancreatic cancer:breaching the stromal fortress by targeting hyaluronic acid. Gut, 2012, 61(10):1377-1379.
38.	Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut, 2011, 60(6):861-868.
39.	Hao K, Tian XD, Qin CF, et al. Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol Rep, 2013, 29(3):1124-1132.
40.	Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 2009, 324(5933):1457-1461.
41.	Onishi H, Katano M. Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J Gastroenterol, 2014, 20(9):2335-2342.
42.	Hilbig A, Oettle H. Transforming growth factor beta in pancreatic cancer. Curr Pharm Biotechnol, 2011, 12(12):2158-2164.
43.	Javle M, Li Y, Tan D, et al. Biomarkers of TGF-β signaling pathway and prognosis of pancreatic cancer. PLoS One, 2014, 9(1):e85942.
44.	Schnurr M, Duewell P. Breaking tumor-induced immunosuppre-ssion with 5'-triphosphate siRNA silencing TGFbeta and activating RIG-I. Oncoimmunology, 2013, 2(5):e24170.
45.	Fuxe J, Karlsson MC. TGF-β-induced epithelial-mesenchymal transition:a link between cancer and inflammation. Semin Cancer Biol, 2012, 22(5-6):455-461.
46.	Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut, 2013, 62(1):112-120.
47.	Fukushige S, Horii A. Road to early detection of pancreatic cancer:attempts to utilize epigenetic biomarkers. Cancer Lett, 2014, 342(2):231-237.
48.	Schneider G, Krämer OH, Saur D. A ZEB1-HDAC pathway enters the epithelial to mesenchymal transition world in pancreatic cancer. Gut, 2012, 61(3):329-330.
49.	Lopez-Serra P, Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene, 2012, 31(13):1609-1622.
50.	Staff C, Mozaffari F, Frödin JE, et al. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int J Oncol, 2014, 45(3):1293-1303.
51.	Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer:a dose escalating phase Ⅰ/Ⅱ study. Br J Cancer, 2006, 95(11):1474-1482.
52.	Middleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac):an open-label, randomised, phase 3 trial. Lancet Oncol, 2014, 15(8):829-840.

1. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2013. Ann Oncol, 2013, 24(3):792-800.
2. Ni X, Yang J, Li M. Imaging-guided curative surgical resection of pancreatic cancer in a xenograft mouse model. Cancer Lett, 2012, 324(2):179-185.
3. Michl P, Gress TM. Current concepts and novel targets in advanced pancreatic cancer. Gut, 2013, 62(2):317-326.
4. Remmers N, Bailey JM, Mohr AM, et al. Molecular pathology of early pancreatic cancer. Cancer Biomark, 2010, 9(1-6):421-440.
5. Wedén S, Klemp M, Gladhaug IP, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer, 2011, 128(5):1120-1128.
6. Deangelo DJ, Neuberg D, Amrein PC, et al. A phase Ⅱ study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia. Leuk Res, 2014, 38(4):430-434.
7. Troiani T, Martinelli E, Capasso A, et al. Targeting EGFR in pancre-atic cancer treatment. Curr Drug Targets, 2012, 13(6):802-810.
8. Vaccaro V, Bria E, Sperduti I, et al. First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer. World J Gastroenterol, 2013, 19(28):4511-4519.
9. Gonçalves A, Gilabert M, François E, et al. BAYPAN study:a double-blind phase Ⅲ randomized trial comparing gemcitabine plus sora-fenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol, 2012, 23(11):2799-2805.
10. Ucar DA, Magis AT, He DH, et al. Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo. Anticancer Agents Med Chem, 2013, 13(4):595-602.
11. Prasad R, Vaid M, Katiyar SK. Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway. PLoS One, 2012, 7(8):e43064.
12. Li J, Liang X, Yang X. Ursolic acid inhibits growth and induces apop-tosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways. Oncol Rep, 2012, 28(2):501-510.
13. Zhang Y, Zhang J, Xu K, et al. PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immunoresistance in pancreatic cancer. Hepatogastroenterology, 2013, 60(127):1766-1772.
14. Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 2013, 23(3):406-420.
15. Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol, 2009, 27(2):193-198.
16. Deeb D, Gao X, Liu YB, et al. Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-κB/mTOR signaling proteins and anti-apoptotic Bcl-2. Int J Oncol, 2014, 44(5):1707-1715.
17. Pollak M. Metformin and pancreatic cancer:a clue requiring investigation. Clin Cancer Res, 2012, 18(10):2723-2725.
18. Bodmer M, Becker C, Meier C, et al. Use of antidiabetic agents and the risk of pancreatic cancer:a case-control analysis. Am J Gastroenterol, 2012, 107(4):620-626.
19. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcrip-tional activation in response to IFNs and other extracellular signa-ling proteins. Science, 1994, 264(5164):1415-1421.
20. Panni RZ, Sanford DE, Belt BA, et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother, 2014, 63(5):513-528.
21. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell, 2011, 19(4):456-469.
22. Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res, 2011, 71(14):5020-5029.
23. Porcelli L, Quatrale AE, Mantuano P, et al. Optimize radiochemo-therapy in pancreatic cancer:PARP inhibitors a new therapeutic opportunity. Mol Oncol, 2013, 7(3):308-322.
24. Yuan K, Sun Y, Zhou T, et al. PARP-1 regulates resistance of pancreatic cancer to TRAIL therapy. Clin Cancer Res, 2013, 19(17):4750-4759.
25. Sawai H, Okada Y, Kazanjian K, et al. The G691S RET polymorp-hism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res, 2005, 65(24):11536-11544.
26. Cavel O, Shomron O, Shabtay A, et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res, 2012, 72(22):5733-5743.
27. Liu H, Ma Q, Li J. High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem, 2011, 347(1-2):95-101.
28. Gil Z, Cavel O, Kelly K, et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst, 2010, 102(2):107-118.
29. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4):252-264.
30. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer, 2012, 12(4):237-251.
31. Koido S, Homma S, Takahara A, et al. Current immunotherapeutic approaches in pancreatic cancer. Clin Dev Immunol, 2011, 2011:267539.
32. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother, 2013, 36(7):382-389.
33. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science, 2011, 331(6024):1612-1616.
34. Vonderheide RH, Bajor DL, Winograd R, et al. CD40 immunoth-erapy for pancreatic cancer. Cancer Immunol Immunother, 2013, 62(5):949-954.
35. Bubenik J, Den Otter W, Huland E. Local cytokine therapy of cancer:interleukin-2, interferons and related cytokines. Cancer Immunol Immunother, 2000, 49(2):116-122.
36. Wagner K, Schulz P, Scholz A, et al. The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clin Cancer Res, 2008, 14(15):4951-4960.
37. Michl P, Gress TM. Improving drug delivery to pancreatic cancer:breaching the stromal fortress by targeting hyaluronic acid. Gut, 2012, 61(10):1377-1379.
38. Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut, 2011, 60(6):861-868.
39. Hao K, Tian XD, Qin CF, et al. Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol Rep, 2013, 29(3):1124-1132.
40. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 2009, 324(5933):1457-1461.
41. Onishi H, Katano M. Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J Gastroenterol, 2014, 20(9):2335-2342.
42. Hilbig A, Oettle H. Transforming growth factor beta in pancreatic cancer. Curr Pharm Biotechnol, 2011, 12(12):2158-2164.
43. Javle M, Li Y, Tan D, et al. Biomarkers of TGF-β signaling pathway and prognosis of pancreatic cancer. PLoS One, 2014, 9(1):e85942.
44. Schnurr M, Duewell P. Breaking tumor-induced immunosuppre-ssion with 5'-triphosphate siRNA silencing TGFbeta and activating RIG-I. Oncoimmunology, 2013, 2(5):e24170.
45. Fuxe J, Karlsson MC. TGF-β-induced epithelial-mesenchymal transition:a link between cancer and inflammation. Semin Cancer Biol, 2012, 22(5-6):455-461.
46. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut, 2013, 62(1):112-120.
47. Fukushige S, Horii A. Road to early detection of pancreatic cancer:attempts to utilize epigenetic biomarkers. Cancer Lett, 2014, 342(2):231-237.
48. Schneider G, Krämer OH, Saur D. A ZEB1-HDAC pathway enters the epithelial to mesenchymal transition world in pancreatic cancer. Gut, 2012, 61(3):329-330.
49. Lopez-Serra P, Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene, 2012, 31(13):1609-1622.
50. Staff C, Mozaffari F, Frödin JE, et al. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int J Oncol, 2014, 45(3):1293-1303.
51. Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer:a dose escalating phase Ⅰ/Ⅱ study. Br J Cancer, 2006, 95(11):1474-1482.
52. Middleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac):an open-label, randomised, phase 3 trial. Lancet Oncol, 2014, 15(8):829-840.

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Therapeutic Targets of Pancreatic Cancer

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