title: Molecular genetics and targeted therapeutics in biliary tract carcinoma.
abstract: The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.
authors.affiliation: Eric I Marks, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, United States.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Marks
authors.affiliation: Eric I Marks, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, United States.
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Biliary tract carcinoma; Cholangiocarcinoma; Gallbladder carcinoma; Molecular genetics; Personalized treatment; Precision therapy; Targeted therapy
references.citation: Gut. 2003 May;52(5):706-12
references.pmid: 12692057
references.citation: Int J Nanomedicine. 2013;8:1697-711
references.pmid: 23658488
references.citation: Nature. 2006 Jan 19;439(7074):358-62
references.pmid: 16273091
references.citation: Lancet. 2014 Jun 21;383(9935):2168-79
references.pmid: 24581682
references.citation: Oncologist. 2012;17(1):72-9
references.pmid: 22180306
references.citation: J Gastroenterol Hepatol. 2014 May;29(5):1119-25
references.pmid: 24372748
references.citation: Cancer. 1995 Jan 1;75(1 Suppl):171-90
references.pmid: 8000995
references.citation: Br J Cancer. 2013 Aug 20;109(4):915-9
references.pmid: 23900219
references.citation: J Hepatobiliary Pancreat Surg. 1999;6(3):237-44
references.pmid: 10526058
references.citation: BMC Cancer. 2010 Nov 18;10:631
references.pmid: 21087480
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3336-40
references.pmid: 9096394
references.citation: Gastroenterology. 2007 Jan;132(1):384-96
references.pmid: 17241887
references.citation: J Cancer Res Clin Oncol. 2005 Oct;131(10):649-52
references.pmid: 16032426
references.citation: World J Gastroenterol. 2005 Jun 28;11(24):3724-8
references.pmid: 15968728
references.citation: J Clin Oncol. 2006 Jul 1;24(19):3069-74
references.pmid: 16809731
references.citation: J Pathol. 2005 Jul;206(3):356-65
references.pmid: 15892172
references.citation: J Clin Oncol. 2011 Jun 10;29(17):2357-63
references.pmid: 21519026
references.citation: Hepatogastroenterology. 2012 Sep;59(118):1769-75
references.pmid: 22172411
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Br J Cancer. 2008 Jan 29;98(2):418-25
references.pmid: 18087285
references.citation: Cancer Chemother Pharmacol. 2009 Sep;64(4):777-83
references.pmid: 19169683
references.citation: Gut. 2000 Nov;47(5):721-7
references.pmid: 11034592
references.citation: Discov Med. 2012 Jul;14(74):41-57
references.pmid: 22846202
references.citation: Langenbecks Arch Surg. 2001 Apr;386(3):224-9
references.pmid: 11382326
references.citation: J Clin Oncol. 2010 Jul 20;28(21):3491-7
references.pmid: 20530271
references.citation: J Gastroenterol Hepatol. 1994 Sep-Oct;9(5):462-7
references.pmid: 7827297
references.citation: Gastroenterology. 2013 Apr;144(4):829-40
references.pmid: 23295441
references.citation: Oncogene. 2008 Sep 18;27(41):5497-510
references.pmid: 18794884
references.citation: Clin Epidemiol. 2014 Mar 07;6:99-109
references.pmid: 24634588
references.citation: Oncology. 2012;82(3):175-9
references.pmid: 22433475
references.citation: Cancer Res Treat. 2005 Jun;37(3):171-6
references.pmid: 19956499
references.citation: CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29
references.pmid: 25559415
references.citation: Oncogene. 2013 Oct 10;32(41):4861-70
references.pmid: 23318457
references.citation: Semin Liver Dis. 2014 Nov;34(4):456-64
references.pmid: 25369307
references.citation: Hepatology. 2004 Apr;39(4):1028-37
references.pmid: 15057907
references.citation: Science. 1998 Nov 13;282(5392):1318-21
references.pmid: 9812896
references.citation: J Clin Pathol. 2010 Dec;63(12):1048-53
references.pmid: 20924037
references.citation: Oncologist. 2002;7 Suppl 4:2-8
references.pmid: 12202782
references.citation: Mod Pathol. 2007 Jun;20(6):701-9
references.pmid: 17431410
references.citation: Genes Chromosomes Cancer. 2008 May;47(5):363-7
references.pmid: 18181165
references.citation: Arch Pathol Lab Med. 2013 Apr;137(4):552-7
references.pmid: 23544944
references.citation: Cancer. 2013 May 1;119(9):1669-74
references.pmid: 23335286
references.citation: Virchows Arch. 2004 Aug;445(2):179-82
references.pmid: 15221372
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1576-83
references.pmid: 17332304
references.citation: Br J Cancer. 2008 Sep 2;99(5):836
references.pmid: 18728674
references.citation: Histol Histopathol. 2005 Jul;20(3):1005-15
references.pmid: 15944951
references.citation: J Transl Med. 2014 Mar 07;12:61
references.pmid: 24606884
references.citation: BMC Cancer. 2011 Feb 08;11:60
references.pmid: 21303542
references.citation: Ann Oncol. 2014 Jun;25(6):1086-97
references.pmid: 24705974
references.citation: Hum Vaccin Immunother. 2013 May;9(5):1069-72
references.pmid: 23376808
references.citation: Oncol Rep. 2009 Aug;22(2):227-32
references.pmid: 19578760
references.citation: Am J Health Syst Pharm. 2008 Sep 15;65(18):1703-10
references.pmid: 18768996
references.citation: Lancet Oncol. 2014 Jul;15(8):819-28
references.pmid: 24852116
references.citation: J Hepatobiliary Pancreat Sci. 2014 Jul;21(7):448-52
references.pmid: 24446428
references.citation: J Gastroenterol. 2011 Jun;46(6):779-89
references.pmid: 21331764
references.citation: Nat Rev Cancer. 2007 Oct;7(10):763-77
references.pmid: 17882277
references.citation: Hum Pathol. 1998 Feb;29(2):175-80
references.pmid: 9490278
references.citation: Lancet Oncol. 2012 Feb;13(2):181-8
references.pmid: 22192731
references.citation: Gastroenterology. 2005 Jun;128(7):2054-65
references.pmid: 15940637
references.citation: World J Gastroenterol. 2006 Jan 21;12(3):415-9
references.pmid: 16489641
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4795-9
references.pmid: 17699857
references.citation: Mod Pathol. 2004 Nov;17(11):1386-91
references.pmid: 15181454
references.citation: Virchows Arch. 2005 Nov;447(5):794-9
references.pmid: 16088402
references.citation: Am J Pathol. 2003 Jul;163(1):217-29
references.pmid: 12819026
references.citation: Hum Pathol. 2013 Jun;44(6):1031-7
references.pmid: 23260331
references.citation: Mod Pathol. 1999 Aug;12(8):763-9
references.pmid: 10463477
references.citation: Gastroenterology. 2013 Dec;145(6):1215-29
references.pmid: 24140396
references.citation: BMC Cancer. 2006 May 10;6:126
references.pmid: 16686942
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references.pmid: 21157483
references.citation: Ann Oncol. 2012 Sep;23(9):2341-2346
references.pmid: 22367707
references.citation: J Clin Oncol. 2010 Jul 20;28(21):3531-40
references.pmid: 20547994
references.citation: Oncologist. 2000;5 Suppl 1:3-10
references.pmid: 10804084
references.citation: Ann Oncol. 2013 Dec;24(12):3061-5
references.pmid: 24146220
references.citation: Histopathology. 2011 Nov;59(5):867-75
references.pmid: 22092398
references.citation: Oncologist. 2008 Apr;13(4):415-23
references.pmid: 18448556
references.citation: Ann Surg. 1998 Mar;227(3):398-404
references.pmid: 9527063
references.citation: Mod Pathol. 2014 Jan;27(1):73-86
references.pmid: 23828315
references.citation: Hum Pathol. 2013 Jul;44(7):1216-22
references.pmid: 23391413
references.citation: J Surg Oncol. 2006 Sep 1;94(3):242-7
references.pmid: 16900513
references.citation: J Natl Compr Canc Netw. 2014 Aug;12(8):1152-82
references.pmid: 25099447
references.citation: Eur J Surg Oncol. 2005 Jun;31(5):533-9
references.pmid: 15922889
references.citation: Clin Cancer Res. 2006 Mar 15;12(6):1680-5
references.pmid: 16551849
references.citation: Hum Pathol. 2008 Aug;39(8):1153-61
references.pmid: 18495210
references.citation: World J Gastroenterol. 2006 Jun 7;12(21):3425-9
references.pmid: 16733863
references.citation: Br J Cancer. 2010 Jan 5;102(1):68-72
references.pmid: 19935794
references.citation: Elife. 2013 Jun 25;2:e00747
references.pmid: 23805382
references.citation: J Gastrointest Oncol. 2013 Mar;4(1):20-9
references.pmid: 23450128
references.citation: Am J Pathol. 2002 Jun;160(6):2073-9
references.pmid: 12057912
references.citation: Lancet Oncol. 2010 Jan;11(1):48-54
references.pmid: 19932054
references.citation: Biol Chem. 2006 Apr;387(4):365-72
references.pmid: 16606333
references.citation: Cancer Manag Res. 2013 Dec 11;9:1-3
references.pmid: 24376362
references.citation: Clin Cancer Res. 2002 Oct;8(10):3156-63
references.pmid: 12374683
references.citation: Br J Cancer. 2002 Aug 12;87(4):432-40
references.pmid: 12177780
references.citation: Semin Liver Dis. 1994 May;14(2):109-14
references.pmid: 8047893
references.citation: N Engl J Med. 2010 Apr 8;362(14):1273-81
references.pmid: 20375404
references.citation: J Surg Oncol. 2000 Mar;73(3):158-63
references.pmid: 10738270
references.citation: Cytokine Growth Factor Rev. 2002 Feb;13(1):41-59
references.pmid: 11750879
references.citation: Methods Enzymol. 2006;407:597-612
references.pmid: 16757355
references.citation: Am J Gastroenterol. 1999 Jun;94(6):1638-42
references.pmid: 10364037
references.citation: Clin Exp Metastasis. 2000;18(5):423-8
references.pmid: 11467775
references.citation: Invest New Drugs. 2013 Aug;31(4):943-8
references.pmid: 23263993