Novel targeted treatment options for advanced cholangiocarcinoma

References

• Saha SK, Zhu AX, Fuchs CS, et al. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594–599.
   PubMed Web of Science ®Google Scholar
• Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011 Jul;54(1):173–184.
   PubMed Web of Science ®Google Scholar
• Silva VWK, Askan G, Daniel TD, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016;5:5.
   PubMed Web of Science ®Google Scholar
• Gu C, Lin YE, Jin H, et al. Biliary papillomatosis with malignant transformation: a case report and review of the literature. Oncol Lett. 2015;10(5):3315–3317.
   PubMed Web of Science ®Google Scholar
• Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015 Sep;47(9):1003–1010.
   PubMed Web of Science ®Google Scholar
• Moeini A, Sia D, Bardeesy N, et al. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22(2):291–300.
   PubMed Web of Science ®Google Scholar
• 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 Jun 20;32(25):3091–3100.
   PubMed Web of Science ®Google Scholar
• Saha SK, Parachoniak CA, Ghanta KS, et al. Corrigendum: mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. Nature. 2015 Dec 3;528(7580):152.
   PubMed Web of Science ®Google Scholar
• DeLeon TT, Ahn DH, Bogenberger JM, et al. Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma. Future Oncol. 2018 Mar;14(6):553–566.
   PubMed Web of Science ®Google Scholar
• Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014 Aug;45(8):1630–1638.
   PubMed Web of Science ®Google Scholar
• Rizvi S, Yamada D, Hirsova P, et al. A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. J Biol Chem. 2016 Apr 8;291(15):8031–8047.
   PubMed Web of Science ®Google Scholar
• Narong S, Leelawat K. Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway. Oncol Lett. 2011 Sep 1;2(5):821–825.
   PubMed Web of Science ®Google Scholar
• Sia D, Losic B, Moeini A, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun. 2015;6:6087.
   PubMed Web of Science ®Google Scholar
• 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 Apr;59(4):1427–1434.
   PubMed Web of Science ®Google Scholar
• Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015;31(3):264–268.
   PubMed Web of Science ®Google Scholar
• Kiguchi K, DiGiovanni J. Role of growth factor signaling pathways in biliary tract cancer. In: Herman JM, Pawlik TM, Thomas JCR, editors. Biliary tract and gallbladder cancer: a multidisciplinary approach. Berlin, Heidelberg: Springer Berlin Heidelberg; 2014. p. 33–44.
   Google Scholar
• Jain A, Borad MJ, Kelley RK, et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precision Oncol. 2018;(2):1–12. DOI:10.1200/PO.17.00080
   Google Scholar
• Miyamoto M, Ojima H, Iwasaki M, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011 Jun 28;105(1):131–138.
   PubMed Web of Science ®Google Scholar
• Miyamoto M, Ojima H, Iwasaki M, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011;105:131.
   PubMed Web of Science ®Google Scholar
• Sia D, Tovar V, Moeini A, et al. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013;32:4861.
   PubMed Web of Science ®Google Scholar
• Sc Wy W, Lui TT, Weng SW, et al. Amplification and overexpression of the MET gene in intrahepatic cholangiocarcinoma correlate with adverse pathological features and worse clinical outcome. Int J Clin Exp Pathol. 2017;10(6):6809–6817.
   Web of Science ®Google Scholar
• 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 Jan;132(1):384–396.
   PubMed Web of Science ®Google Scholar
• Park J, Tadlock L, Gores GJ, et al. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology. 1999 Nov;30(5):1128–1133.
   PubMed Web of Science ®Google Scholar
• Wehbe H, Henson R, Meng F, et al. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res. 2006 Nov 1;66(21):10517–10524.
   PubMed Web of Science ®Google Scholar
• Pignochino Y, Sarotto I, Peraldo-Neia C, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer. 2010;10(1):631.
   PubMed Web of Science ®Google Scholar
• 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 Feb;10(2):e1004135.
   PubMed Web of Science ®Google Scholar
• Andrici J, Goeppert B, Sioson L, et al. Loss of BAP1 expression occurs frequently in intrahepatic cholangiocarcinoma. Medicine. 2016;;95(2):e2491.
   PubMed Web of Science ®Google Scholar
• Misumi K, Hayashi A, Shibahara J, et al. Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression, and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss. Histopathology. 2017;70(5):766–774.
   PubMed Web of Science ®Google Scholar
• Anand D, Churi C, Rashid A, et al. BAP1 mutation-associated cholangiocarcinoma: an aggressive disease. J Clin Oncol. 2015;33(3_suppl): 420–420. doi: 10.1200/jco.2015.33.3_suppl.420.
   Web of Science ®Google Scholar
• Boulter L, Guest RV, Kendall TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015 Mar 2;125(3):1269–1285.
   PubMed Web of Science ®Google Scholar
• Goeppert B, Konermann C, Schmidt CR, et al. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology. 2014 Feb;59(2):544–554.
   PubMed Web of Science ®Google Scholar
• Putra J, De Abreu FB, Peterson JD, et al. Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing. Exp Mol Pathol. 2015;99(2):240–244.
   PubMed Web of Science ®Google Scholar
• Wiggers JK, Ruys AT, Groot Koerkamp B, et al. Differences in immunohistochemical biomarkers between intra- and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2014 Aug;29(8):1582–1594.
   PubMed Web of Science ®Google Scholar
• Yoshikawa D, Ojima H, Iwasaki M, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer 2007:98:418. https://www.nature.com/articles/6604129#supplementary-information
   PubMed Web of Science ®Google Scholar
• Javle M, Churi C, Kang HC, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8(1):58.
   PubMed Web of Science ®Google Scholar
• Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?. Cancer Metastasis Rev. 2017;36(1):141–157.
   PubMed Web of Science ®Google Scholar
• Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9(12):e115383.
   PubMed Web of Science ®Google Scholar
• Lee H, Ross JS. The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer. Therap Adv Gastroenterol. 2017;10(6):507–520.
   PubMed Web of Science ®Google Scholar
• Kubicka S, Rudolph KL, Tietze MK, et al. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology. 2001 May-Jun;48(39):783–789.
   PubMed Web of Science ®Google Scholar
• Mezger J, Sauerbruch T, Ko Y, et al. Phase II study with gemcitabine in gallbladder and biliary tract carcinomasa. Oncol Res Treat. 1998;21(3):232–234.
   Google Scholar
• Penz M, Kornek GV, Raderer M, et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol. 2001 Feb;12(2):183–186.
   PubMed Web of Science ®Google Scholar
• Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol. 2005 Apr 1;23(10):2332–2338.
   PubMed Web of Science ®Google Scholar
• Cho JY, Paik YH, Chang YS, et al. Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer. 2005 Dec 15;104(12):2753–2758.
   PubMed Web of Science ®Google Scholar
• Riechelmann RP, Townsley CA, Chin SN, et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer. 2007 Sep 15;110(6):1307–1312.
   PubMed Web of Science ®Google Scholar
• Chae YK, Ranganath K, Hammerman PS, et al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017;8(9):16052–16074.
   PubMedGoogle Scholar
• Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose escalation and expansion cohorts. J Clin Oncol. 2017;35(15_suppl): 4015–4015.
   Google Scholar
• Meyerhardt JA, Zhu AX, Stuart K, et al. Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer. Dig Dis Sci. 2008 Feb;53(2):564–570.
   PubMed Web of Science ®Google Scholar
• Thongprasert S, Napapan S, Charoentum C, et al. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol. 2005 Feb;16(2):279–281.
   PubMed Web of Science ®Google Scholar
• Kim ST, Park JO, Lee J, et al. A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer. 2006 Mar 15;106(6):1339–1346.
   PubMed Web of Science ®Google Scholar
• Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–1281.
   PubMed Web of Science ®Google Scholar
• Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004 Sep;15(9):1339–1343.
   PubMed Web of Science ®Google Scholar
• Harder J, Riecken B, Kummer O, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006 Oct 9;95(7):848–852.
   PubMed Web of Science ®Google Scholar
• Gebbia N, Verderame F, Di Leo R, et al. A phase II study of oxaliplatin (O) and gemcitabine (G) first line chemotherapy in patients with advanced biliary tract cancers. J Clin Oncol. 2005;23(16_suppl): 4132–4132.
   Google Scholar
• Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–282.
   PubMed Web of Science ®Google Scholar
• Miyano SW, Arai Y, Matsui J, et al. Abstract 2095: E7090, a novel and selective FGFR inhibitor, for the treatment of cholangiocarcinoma cells harboring FGFR2-fusion genes. Cancer Res. 2017;77(13 Supplement): 2095–2095.
   PubMedGoogle Scholar
• Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2016;35(2):157–165.
   PubMed Web of Science ®Google Scholar
• Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2017;36(3):276–282.
   PubMed Web of Science ®Google Scholar
• Papadopoulos KP, El-Rayes BF, Tolcher AW, et al. A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017;117(11):1592–1599.
   PubMed Web of Science ®Google Scholar
• Mazzaferro V, El-Rayes BF, Cotsoglou C, et al. ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. J Clin Oncol. 2017;35(15_suppl): 4017–4017.
   Google Scholar
• Goyal L, Arkenau H-T, Tran B, et al. O-020 early clinical efficacy of TAS-120, a covalently bound FGFR inhibitor, in patients with cholangiocarcinoma. Ann Oncol. 2017;28(suppl_3):mdx262.019-mdx262.019.
   Google Scholar
• Saleh M, Gutierrez ME, Subbiah V, et al. Abstract CT111: preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced malignancies. Cancer Res. 2017;77(13Supplement):CT111–CT111.
   Google Scholar
• Borad MJ, Davis SL, Lowery MA, et al. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy. J Clin Oncol. 2017;35(15_suppl):TPS4145–TPS4145.
   Google Scholar
• Zhao WM, Wang L, Park H, et al. Monoclonal antibodies to fibroblast growth factor receptor 2 effectively inhibit growth of gastric tumor xenografts. Clin Cancer Res. 2010 Dec 1;16(23):5750–5758.
   PubMed Web of Science ®Google Scholar
• Acquaviva J, He S, Zhang C, et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol Cancer Res. 2014 Jul;12(7):1042–1054.
   PubMed Web of Science ®Google Scholar
• Ishii Y, Sigel C, Lowery MA, et al. Abstract A071: AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor, promotes morphologic changes and upregulates liver-specific genes in IDH1 mutant cholangiocarcinoma. Mol Cancer Ther. 2018;17(1 Supplement):A071–A071.
   Google Scholar
• Lowery MA, Abou-Alfa GK, Valle JW, et al. ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation. J Clin Oncol. 2017;35(15_suppl):TPS4142–TPS4142.
   Google Scholar
• Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013 Feb;3(2):224–237.
   PubMed Web of Science ®Google Scholar
• Ding X, Chaiteerakij R, Moser CD, et al. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. Oncotarget. 2016 Apr 12;7(15):20080–20092.
   PubMedGoogle Scholar
• Britten CD, Thomas MB, Garrett-Mayer E, et al. A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2017 Aug 15;23(16):4642–4650.
   PubMedGoogle Scholar
• Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006 Jul 1;24(19):3069–3074.
   PubMed Web of Science ®Google Scholar
• Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014 Jul;15(8):819–828.
   PubMed Web of Science ®Google Scholar
• Sohal DP, Mykulowycz K, Uehara T, et al. A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Ann Oncol. 2013 Dec;24(12):3061–3065.
   PubMed Web of Science ®Google Scholar
• Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016 Feb 15;122(4):574–581.
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Rankin C, Lenz HJ, et al. SWOG 0514: A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas. J Clin Oncol. 2007;25(18_suppl): 4639–4639.
   PubMedGoogle Scholar
• Sun W, Normolle DP, Bahary N, et al. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy refractory advanced and metastatic biliary adenocarcinoma/cholangiocarcinoma. J Clin Oncol. 2017;35(15_suppl): 4081–4081.
   Google Scholar
• Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010 Jan;11(1):48–54.
   PubMed Web of Science ®Google Scholar
• 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 Jul 20;28(21):3491–3497.
   PubMed Web of Science ®Google Scholar
• Brechon M, Dior M, Dreanic J, et al. Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers. Invest New Drugs. 2017 Aug 1. DOI:10.1007/s10637-017-0492-6.
   PubMed Web of Science ®Google Scholar
• J-F G-D, Lorgis V, Vincent J, et al. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol. 2015;21(7):2096–2101.
   PubMed Web of Science ®Google Scholar
• Bekaii-Saab T, Phelps MA, Li X, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29(17):2357–2363.
   PubMed Web of Science ®Google Scholar
• Bendell JC, Javle M, Bekaii-Saab TS, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor [Clinical Study]. Br J Cancer. 2017;116:575.
   PubMed Web of Science ®Google Scholar
• Kocsis J, Árokszállási A, András C, et al. Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion. J Gastrointest Oncol. 2017;8(2):E32–E38.
   PubMed Web of Science ®Google Scholar
• Lavingia V, Fakih M. Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma—2 case reports and a brief review. J Gastrointest Oncol. 2016;7(6):E98–E102.
   PubMed Web of Science ®Google Scholar
• Kim RD, McDonough SL, El-Khoueiry AB, et al. SWOG S1310: randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer. J Clin Oncol. 2017;35(15_suppl): 4016–4016.
   Google Scholar
• Daya M, Loilome W, Techasen A, et al. Progranulin modulates cholangiocarcinoma cell proliferation, apoptosis, and motility via the PI3K/pAkt pathway. Onco Targets Ther. 2018;11:395–408.
   PubMed Web of Science ®Google Scholar
• Wilson JM, Kunnimalaiyaan S, Kunnimalaiyaan M, et al. Inhibition of the AKT pathway in cholangiocarcinoma by MK2206 reduces cellular viability via induction of apoptosis. Cancer Cell Int. 2015;15(1):13.
   PubMedGoogle Scholar
• Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009 Aug;9(8):550–562.
   PubMed Web of Science ®Google Scholar
• Ewald F, Grabinski N, Grottke A, et al. Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma. Int J Cancer. 2013 Nov;133(9):2065–2076.
   PubMed Web of Science ®Google Scholar
• Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011 Dec 10;29(35):4688–4695.
   PubMed Web of Science ®Google Scholar
• Grabinski N, Ewald F, Hofmann BT, et al. Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells. Mol Cancer. 2012;11:85.
   PubMed Web of Science ®Google Scholar
• Ahn DH, Li J, Wei L, et al. Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer. Sci Rep. 2015;5:12122.
   PubMed Web of Science ®Google Scholar
• Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012;30:677–706.
   PubMed Web of Science ®Google Scholar
• Goldstein D, Lemech C, Valle J. New molecular and immunotherapeutic approaches in biliary cancer. ESMO Open. 2017;2(Suppl1). doi: 10.1136/esmoopen-2016-000152.
   PubMedGoogle Scholar
• Fontugne J, Augustin J, Pujals A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget. 2017;8(15):24644–24651.
   PubMedGoogle Scholar
• Walter D, Herrmann E, Schnitzbauer AA, et al. PD-L1 expression in extrahepatic cholangiocarcinoma. Histopathology. 2017 Sep;71(3):383–392.
   PubMed Web of Science ®Google Scholar
• Kim R, Coppola D, Wang E, et al. Prognostic value of CD8CD45RO tumor infiltrating lymphocytes in patients with extrahepatic cholangiocarcinoma. Oncotarget. 2018 May 4;9(34):23366–23372..
   PubMedGoogle Scholar
• Lange S, Lampe J, Bossow S, et al. A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma. Hum Gene Ther. 2013;24(5):554–564.
   PubMed Web of Science ®Google Scholar
• Marks EI, Yee NS. Immunotherapeutic approaches in biliary tract carcinoma: current status and emerging strategies. World J Gastrointest Oncol. 2015;7(11):338–346.
   PubMed Web of Science ®Google Scholar
• Bang YJ, Doi T, Braud FD, et al. 525 safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer. 51:S112. doi: 10.1016/S0959-8049(16)30326-4.
   PubMedGoogle Scholar
• Lin J, Shi W, Zhao S, et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): preliminary data and correlation with next-generation sequencing. J Clin Oncol. 2018;36(4_suppl): 500–500.
   Web of Science ®Google Scholar
• Sahai V, Griffith KA, Zalupski M. A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer. J Clin Oncol. 2018;36(4_suppl):TPS541–TPS541.
   Web of Science ®Google Scholar
• Silva VW, Askan G, Daniel TD, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016 Oct;5(5):62.
   PubMed Web of Science ®Google Scholar