Targeted treatment of pancreas carcinoma – past or future?

Česká verzia

Authors: T. Hucl
Authors place of work: Klinika hepatogastroenterologie, IKEM, Praha
Published in the journal: Gastroent Hepatol 2013; 67(5): 366-376
Category: Gastrointestinal Oncology: Review Article

Summary

Pancreas carcinoma is a disease with an increasing occurrence and a devastating prognosis. The main cause of the unfavourable prognosis is late diagnosis which most frequently occurs in the state of generalisation and resistance to the currently used chemotherapy. The currently used chemotherapeutical regimes have a non-specific impact on carcinoma; they are administered with a palliative effect and lead only to a marginal improvement in the survival rate. The lack of a curable treatment means that less than 5% of patients survive five years. The targeted treatment aims to find signal paths, which are only active in the carcinoma and entirely necessary for its occurrence or progression. Progress in our understanding of molecular and biological processes characterising pancreas carcinoma and success in the targeted treatment of other tumour diseases led to an effort to find a targeted treatment for pancreas carcinoma. During the last decade a number of targeted chemotherapeutics were tested. However, their clinical significance has so far been only limited and we are still waiting for an effective targeted treatment. Closer understanding of molecular mechanisms of pathogenesis and identification of new suitable goals and molecules for inhibition in selected patients represent the highest potential for the future treatment of pancreas carcinoma.

Key words:
pancreas carcinoma – signal path – targeted treatment

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
27. 8. 2013

Accepted:
1. 10. 2013

Zdroje

1. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20(2): 197–209.

2. Hucl T. Karcinom pankreatu. Gastroent Hepatol 2012; 66(5): 350–356.

3. Hucl T, Brody JR, Gallmeier E et al. High cancer-specific expression of mesothelin (MSLN) is attributable to an upstream enhancer containing a transcription enhancer factor dependent MCAT motif. Cancer Res 2007; 67(19): 9055–9065.

4. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321(5897): 1801–1806.

5. Van Laethem JL, Verslype C, Iovanna JL et al. New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. Ann Oncol 2012; 23(3): 570–576.

6. Burris HA 3rd, Moore MJ, Andersen J 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(6): 2403–2413.

7. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364(19): 1817–1825.

8. Von Hoff DD et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol 2012; 30: LBA148.

9. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344(14): 1038–1042.

10. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344(14): 1031–1037.

11. Hucl T, Rago C, Gallmeier E et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res 2008; 68(13): 5023–5030.

12. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull 2008; 87: 97–130.

13. Almoguera C, Shibata D, Forrester K et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988; 53(4): 549–554.

14. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989; 49(17): 4682–4689.

15. Zagouri F, Sergentanis TN, Chrysikos D et al. Molecularly targeted therapies in metastatic pancreatic cancer: a systematic review. Pancreas 2013; 42(5): 760–773.

16. End DW, Smets G, Todd AV et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61(1): 131–137.

17. Crul M, de Klerk GJ, Swart M et al. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2002; 20(11): 2726–2735.

18. Cohen SJ, Ho L, Ranganathan S 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(7): 1301–1306.

19. Macdonald JS, McCoy S, Whitehead RP 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(5): 485–487.

20. Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22(8): 1430–1438.

21. Hong DS, Sebti SM, Newman RA et al. Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clin Cancer Res 2009; 15(22): 7061–7068.

22. Lobell RB, Liu D, Buser CA et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl: protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 2002; 1(9): 747–758.

23. Downward J, Yarden Y, Mayes E et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984; 307(5951): 521–527.

24. Bloomston M, Bhardwaj A, Ellison EC et al. Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique. Dig Surg 2006; 23(1–2): 74–79.

25. Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 2004; 3(10): 1221–1224.

26. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129–2139.

27. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20 (18 Suppl): 1S–13S.

28. Xiong HQ, Rosenberg A, LoBuglio A 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(13): 2610–2616.

29. 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; 28(22): 3605–3610.

30. Kullmann F, Hartmann A, Stöhr R et al. KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy. Oncology 2011; 81(1): 3–8.

31. Graeven U, Kremer B, Südhoff T et al. Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. Br J Cancer 2006; 94(9): 1293–1299.

32. Vanhoefer U, Tewes M, Rojo F et al. Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 2004; 22(1): 175–184.

33. 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; 25(15): 1960–1966.

34. Fountzilas G, Bobos M, Kalogera-Fountzila A et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Invest 2008; 26(8): 784–793.

35. Gharibo M, Patrick-Miller L, Zheng L et al. A phase II trial of imatinib mesylate in patients with metastatic pancreatic cancer. Pancreas 2008; 36(4): 341–345.

36. Chen J, Röcken C, Nitsche B et al. The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. Cancer Lett 2006; 233(2): 328–337.

37. Yamanaka Y, Friess H, Kobrin MS et al. Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol 1993; 24(10): 1127–1134.

38. 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.

39. Agus DB, Gordon MS, Taylor C et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005; 23(11): 2534–2543.

40. Safran H, Miner, T, Bahary N et al. Lapatinib and gemcitabine for metastatic pancreatic cancer: a phase II study. ASCO Meeting Abstracts 2009; 27: e15653.

41. Cheng JQ, Ruggeri B, Klein WM et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 1996; 93(8): 3636–3641.

42. Richards DA, Kuefler PR, Becerra C et al. Gemcitabine plus enzastaurin or single--agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Invest New Drugs 2011; 29(1): 144–153.

43. Ito D, Fujimoto K, Mori T et al. In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer 2006; 118(9): 2337–2343.

44. Javle MM, Shroff RT, Xiong H et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer 2010; 10: 368.

45. Garrido-Laguna I, Rudek M, Tan A et al. Preclinical identification of biomarkers of response to mTOR inhibitors and subsequent application in a phase II trail of sirolimus in pancreatic cancer patients refractory to gemcitabine. ASCO Meeting Abstracts 2009; 27: 4612.

46. Seo Y, Baba H, Fukuda T et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000; 88(10): 2239–2245.

47. 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; 28(22): 3617–3622.

48. 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; 27(13): 2231–2237.

49. Lubner SJ, Schelman WR, Mulkerin D et al. Phase II study of oxaliplatin, high-dose capecitabine, and sorafenib in patients with advanced pancreatic cancer. ASCO Meeting Abstracts 2010; 28: 4143.

50. O'Reilly EM, Niedzwiecki D, Hall M et al. A Cancer and Leukemia Group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). Oncologist 2010; 15(12): 1310–1319.

51. Kindler HL, Ioka T, Richel DJ 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(3): 256–262.

52. Bramhall SR, Rosemurgy A, Brown PD et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001; 19(15): 3447–3455.

53. Bramhall SR, Schulz J, Nemunaitis J et al. 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(2): 161–167.

54. Tucker ON, Dannenberg AJ, Yang EK et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999; 59(5): 987–990.

55. Molina MA, Sitja-Arnau M, Lemoine MG et al. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 1999; 59(17): 4356–4362.

56. Xiong HQ, Plunkett W, Wolff R et al. A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 2005; 55(6): 559–564.

57. Ferrari V, Valcamonico F, Amoroso V et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 2006; 57(2): 185–190.

58. Dragovich T, Burris H 3rd, Loehrer P et al. Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am J Clin Oncol 2008; 31(2): 157–162.

59. Milella M, Gelibter A, Di Cosimo S et al. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004; 101(1): 133–138.

60. Armstrong DK, Laheru, D, Ma WW et al. A phase I clinical study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma and ovarian adenocarcinoma. ASCO Meeting Abstracts 2007; 25: 14041.

61. Wang W, Abbruzzese JL, Evans DB et al. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5(1): 119–127.

62. Shah SA, Potter MW, McDade TP et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001; 82(1): 110–122.

63. Alberts SR, Foster NR, Morton RF et al. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol 2005; 16(10): 1654–1661.

64. Dhillon N, Aggarwal BB, Newman RA et al. Curcumin and pancreatic cancer: Phase II clinical trial experience. ASCO Meeting Abstracts 2007; 25: 4599.

65. Hucl T, Gallmeier E. DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res 2011; 60(3): 453–465.

66. Howlett NG, Taniguchi T, Olson S et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002; 297(5581): 606–609.

67. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62(3): 676–689.

68. Hahn SA, Greenhalf B, Ellis I et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003; 95(3): 214–221.

69. Van der Heijden MS, Yeo CJ, Hruban RH et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 2003; 63(10): 2585–2588.

70. Tischkowitz MD, Sabbaghian N, Hamel N et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology 2009; 137(3): 1183–1186.

71. Jones S, Hruban RH, Kamiyama M et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009; 324(5924): 217.

72. Tuinmann G, Hegewisch-Becker S, Zschaber R et al. Gemcitabine and mitomycin C in advanced pancreatic cancer: a single-institution experience. Anticancer Drugs 2004; 15(6): 575–579.

73. Chalasani P, Kurtin S, Dragovich T. Response to a third-line mitomycin C (MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germline BRCA2 mutation. JOP 2008; 9(3): 305–308.

74. Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434(7035): 913–917.

75. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434(7035): 917–921.

76. O’Reilly EM LA, Yu KH et al. Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC). J Clin Oncol 2013; 31: TPS4144.

77. Thayer SP, di Magliano MP, Heiser PW et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425(6960): 851–856.

78. 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.

79. Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med 2009; 361(21): 2094–2096.

80. Sandhiya S, Melvin G, Kumar SS et al. The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother 2013; 4(1): 4–7.

81. Thomas AM, Santarsiero LM, Lutz ER et al. Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 2004; 200(3): 297–306.

82. Da Cunha Santos G, Dhani N, Tu D et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer 2010; 116(24): 5599–5607.

83. Lievre A, Bachet JB, Le Corre D et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66(8): 3992–3995.

84. 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; 10(1): 3–8.