Download PDF
Semin Liver Dis 2014; 34(04): 456-464
DOI: 10.1055/s-0034-1394144
Review Article

Cholangiocarcinoma: Molecular Pathways and Therapeutic Opportunities

Sumera I Ilyas
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
,
Mitesh J. Borad
2   Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona
,
Tushar Patel
3   Departments of Internal Medicine, Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida
,
Gregory J. Gores
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
› Further Information
    Permissions and Reprints

Corrected by:

Erratum: Cholangiocarcinoma: Molecular Pathways and Therapeutic OpportunitiesSemin Liver Dis 2014; 34(04): e1-e1
DOI: 10.1055/s-0044-1786507

Abstract

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.

Keywords

cholangiocarcinoma - molecular pathogenesis - targeted therapy


Publication History

Publication Date:
04 November 2014 (online)

© 2014. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145 (6) 1215-1229
    Google Scholar
  • 2 Sirica AE, Gores GJ. Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology 2014; 59 (6) 2397-2402
    Google Scholar
  • 3 Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383 (9935) 2168-2179
    Google Scholar
  • 4 Farley DR, Weaver AL, Nagorney DM. “Natural history” of unresected cholangiocarcinoma: patient outcome after noncurative intervention. Mayo Clin Proc 1995; 70 (5) 425-429
    Google Scholar
  • 5 Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas. Gastroenterology 2009; 136 (4) 1134-1144
    Google Scholar
  • 6 Valle J, Wasan H, Palmer DH. , et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362 (14) 1273-1281
    Google Scholar
  • 7 Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011; 54 (1) 173-184
    Google Scholar
  • 8 Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000; 60 (1) 184-190
    Google Scholar
  • 9 Jaiswal M, LaRusso NF, Shapiro RA, Billiar TR, Gores GJ. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology 2001; 120 (1) 190-199
    Google Scholar
  • 10 Haigh WG, Lee SP. Identification of oxysterols in human bile and pigment gallstones. Gastroenterology 2001; 121 (1) 118-123
    Google Scholar
  • 11 Kuver R. Mechanisms of oxysterol-induced disease: insights from the biliary system. Clin Lipidol 2012; 7 (5) 537-548
    Google Scholar
  • 12 Dwyer JR, Sever N, Carlson M, Nelson SF, Beachy PA, Parhami F. Oxysterols are novel activators of the Hedgehog signaling pathway in pluripotent mesenchymal cells. J Biol Chem 2007; 282 (12) 8959-8968
    Google Scholar
  • 13 Nachtergaele S, Mydock LK, Krishnan K. , et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat Chem Biol 2012; 8 (2) 211-220
    Google Scholar
  • 14 Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology 2002; 122 (4) 985-993
    Google Scholar
  • 15 Yoon JH, Canbay AE, Werneburg NW, Lee SP, Gores GJ. Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: implications for biliary tract carcinogenesis. Hepatology 2004; 39 (3) 732-738
    Google Scholar
  • 16 Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2012; 28 (3) 266-272
    Google Scholar
  • 17 Ong CK, Subimerb C, Pairojkul C. , et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet 2012; 44 (6) 690-693
    Google Scholar
  • 18 Chan-On W, Nairismägi ML, Ong CK. , et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet 2013; 45 (12) 1474-1478
    Google Scholar
  • 19 Jiao Y, Pawlik TM, Anders RA. , et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013; 45 (12) 1470-1473
    Google Scholar
  • 20 Gao Q, Zhao YJ, Wang XY. , et al. Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology 2014; 146 (5) 1397-1407
    Google Scholar
  • 21 Sia D, Hoshida Y, Villanueva A. , et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013; 144 (4) 829-840
    Google Scholar
  • 22 Andersen JB, Spee B, Blechacz BR. , et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012; 142 (4) 1021-1031 , e15
    Google Scholar
  • 23 Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 2013; 32 (41) 4861-4870
    Google Scholar
  • 24 Khan SA, Thomas HC, Toledano MB, Cox IJ, Taylor-Robinson SD. p53 Mutations in human cholangiocarcinoma: a review. Liver Int 2005; 25 (4) 704-716
    Google Scholar
  • 25 Tannapfel A, Sommerer F, Benicke M. , et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003; 52 (5) 706-712
    Google Scholar
  • 26 Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology 2005; 128 (7) 2054-2065
    Google Scholar
  • 27 Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 1999; 30 (5) 1128-1133
    Google Scholar
  • 28 Taniai M, Grambihler A, Higuchi H. , et al. Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 2004; 64 (10) 3517-3524
    Google Scholar
  • 29 Isomoto H, Kobayashi S, Werneburg NW. , et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005; 42 (6) 1329-1338
    Google Scholar
  • 30 Isomoto H, Mott JL, Kobayashi S. , et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 2007; 132 (1) 384-396
    Google Scholar
  • 31 Genovese MC, Fleischmann R, Furst D. , et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis 2014; 73 (9) 1607-1615
    Google Scholar
  • 32 Tanaka Y, Martin Mola E. IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis 2014; 73 (9) 1595-1597
    Google Scholar
  • 33 Abulwerdi F, Liao C, Liu M. , et al. A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 2014; 13 (3) 565-575
    Google Scholar
  • 34 Abulwerdi FA, Liao C, Mady AS. , et al. 3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation. J Med Chem 2014; 57 (10) 4111-4133
    Google Scholar
  • 35 Yu C, Bruzek LM, Meng XW. , et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005; 24 (46) 6861-6869
    Google Scholar
  • 36 Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010; 137 (23) 4061-4072
    Google Scholar
  • 37 Ishimura N, Bronk SF, Gores GJ. Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis. Gastroenterology 2005; 128 (5) 1354-1368
    Google Scholar
  • 38 Fan B, Malato Y, Calvisi DF. , et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest 2012; 122 (8) 2911-2915
    Google Scholar
  • 39 Sekiya S, Suzuki A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J Clin Invest 2012; 122 (11) 3914-3918
    Google Scholar
  • 40 Zender S, Nickeleit I, Wuestefeld T. , et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 2013; 23 (6) 784-795
    Google Scholar
  • 41 Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol 2014; 60 (4) 885-890
    Google Scholar
  • 42 Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol 2008; 14 (46) 7033-7058
    Google Scholar
  • 43 Kiguchi K, Carbajal S, Chan K. , et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001; 61 (19) 6971-6976
    Google Scholar
  • 44 Graham RP, Barr Fritcher EG, Pestova E. , et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 2014; 45 (8) 1630-1638
    Google Scholar
  • 45 Lubner SJ, Mahoney MR, Kolesar JL. , et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol 2010; 28 (21) 3491-3497
    Google Scholar
  • 46 Philip PA, Mahoney MR, Allmer C. , et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 2006; 24 (19) 3069-3074
    Google Scholar
  • 47 Voss JS, Holtegaard LM, Kerr SE. , et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol 2013; 44 (7) 1216-1222
    Google Scholar
  • 48 Borad MJ, Champion MD, Egan JB. , et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 2014; 10 (2) e1004135
    Google Scholar
  • 49 Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008; 7 (6) 504-516
    Google Scholar
  • 50 Appleman LJ. MET signaling pathway: a rational target for cancer therapy. J Clin Oncol 2011; 29 (36) 4837-4838
    Google Scholar
  • 51 Ross JS, Wang K, Gay L. , et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 2014; 19 (3) 235-242
    Google Scholar
  • 52 Gu TL, Deng X, Huang F. , et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS ONE 2011; 6 (1) e15640
    Google Scholar
  • 53 Saborowski A, Saborowski M, Davare MA, Druker BJ, Klimstra DS, Lowe SW. Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci U S A 2013; 110 (48) 19513-19518
    Google Scholar
  • 54 Davare MA, Saborowski A, Eide CA. , et al. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A 2013; 110 (48) 19519-19524
    Google Scholar
  • 55 Arai Y, Totoki Y, Hosoda F. , et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014; 59 (4) 1427-1434
    Google Scholar
  • 56 Wu YM, Su F, Kalyana-Sundaram S. , et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013; 3 (6) 636-647
    Google Scholar
  • 57 Guagnano V, Kauffmann A, Wöhrle S. , et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012; 2 (12) 1118-1133
    Google Scholar
  • 58 Escudier B, Grünwald V, Ravaud A. , et al. Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res 2014; 20 (11) 3012-3022
    Google Scholar
  • 59 Grassian AR, Pagliarini R, Chiang DY. Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2014; 30 (3) 295-302
    Google Scholar
  • 60 Kipp BR, Voss JS, Kerr SE. , et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol 2012; 43 (10) 1552-1558
    Google Scholar
  • 61 Wang P, Dong Q, Zhang C. , et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 2013; 32 (25) 3091-3100
    Google Scholar
  • 62 Rohle D, Popovici-Muller J, Palaskas N. , et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340 (6132) 626-630
    Google Scholar
  • 63 Wang F, Travins J, DeLaBarre B. , et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340 (6132) 622-626
    Google Scholar
  • 64 Xu RF, Sun JP, Zhang SR. , et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother 2011; 65 (1) 22-26
    Google Scholar
  • 65 Meng F, Henson R, Lang M. , et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 2006; 130 (7) 2113-2129
    Google Scholar
  • 66 Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog 2012; 17 (1) 69-95
    Google Scholar
  • 67 Liu N, Rowley BR, Bull CO. , et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther 2013; 12 (11) 2319-2330
    Google Scholar
  • 68 Wallin JJ, Edgar KA, Guan J. , et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011; 10 (12) 2426-2436
    Google Scholar
  • 69 Costello BA, Borad MJ, Qi Y. , et al. Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Invest New Drugs 2014; 32 (4) 710-716
    Google Scholar
  • 70 Ma X, Ezzeldin HH, Diasio RB. Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 2009; 69 (14) 1911-1934
    Google Scholar
  • 71 Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2012; 9 (1) 44-54
    Google Scholar
  • 72 DeClerck YA. Desmoplasia: a response or a niche?. Cancer Discov 2012; 2 (9) 772-774
    Google Scholar
  • 73 Ling H, Roux E, Hempel D. , et al. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLoS ONE 2013; 8 (1) e54499
    Google Scholar
  • 74 Pinlaor S, Prakobwong S, Hiraku Y, Pinlaor P, Laothong U, Yongvanit P. Reduction of periductal fibrosis in liver fluke-infected hamsters after long-term curcumin treatment. Eur J Pharmacol 2010; 638 1-3 134-141
    Google Scholar
  • 75 Mertens JC, Fingas CD, Christensen JD. , et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 2013; 73 (2) 897-907
    Google Scholar
  • 76 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
    Google Scholar
  • 77 Garber K. Stromal depletion goes on trial in pancreatic cancer. J Natl Cancer Inst 2010; 102 (7) 448-450
    Google Scholar
  • 78 Clapéron A, Mergey M, Aoudjehane L. , et al. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor. Hepatology 2013; 58 (6) 2001-2011
    Google Scholar
  • 79 Fingas CD, Bronk SF, Werneburg NW. , et al. Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 2011; 54 (6) 2076-2088
    Google Scholar
  • 80 Fingas CD, Mertens JC, Razumilava N, Bronk SF, Sirica AE, Gores GJ. Targeting PDGFR-β in cholangiocarcinoma. Liver Int 2012; 32 (3) 400-409
    Google Scholar
  • 81 Wiedmann MW, Mössner J. Molecular targeted therapy of biliary tract cancer–results of the first clinical studies. Curr Drug Targets 2010; 11 (7) 834-850
    Google Scholar
  • 82 Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012; 366 (26) 2517-2519
    Google Scholar