EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber-modified adenovirus
Rei Kawashima
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorCorresponding Author
Masato Abei
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Tel.: 81-298-53-3125, Fax: +81-298-53-3218
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, JapanSearch for more papers by this authorKuniaki Fukuda
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorKiminori Nakamura
Department of Molecular Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan
Search for more papers by this authorTakehide Murata
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorMariko Wakayama
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorEmiko Seo
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorNaoyuki Hasegawa
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorHiroyuki Mizuguchi
Department of Biotechnology and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorYuichi Obata
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorIchinosuke Hyodo
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorHirofumi Hamada
Department of Molecular Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan
Search for more papers by this authorKazunari K. Yokoyama
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Center of Excellence for Environmental Medicine, Cancer Center, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Search for more papers by this authorRei Kawashima
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorCorresponding Author
Masato Abei
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Tel.: 81-298-53-3125, Fax: +81-298-53-3218
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, JapanSearch for more papers by this authorKuniaki Fukuda
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorKiminori Nakamura
Department of Molecular Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan
Search for more papers by this authorTakehide Murata
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorMariko Wakayama
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorEmiko Seo
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorNaoyuki Hasegawa
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorHiroyuki Mizuguchi
Department of Biotechnology and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorYuichi Obata
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Search for more papers by this authorIchinosuke Hyodo
Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8575, Japan
Search for more papers by this authorHirofumi Hamada
Department of Molecular Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan
Search for more papers by this authorKazunari K. Yokoyama
Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki 305-0074, Japan
Center of Excellence for Environmental Medicine, Cancer Center, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Search for more papers by this authorAbstract
A critical issue in adenovirus (Ad)-based cancer gene therapy is to improve the specificity of gene delivery to cancer cells for better efficacy and safety. We explored methods of retargeting Ad vectors for selective gene therapy of human biliary cancers using the Ad incorporating an IgG Fc-binding motif (Z33) from the Staphylococcus protein A (Ad-FZ33) combined with tumor-specific antibodies. Flow cytometry analysis revealed high-expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) on human biliary cancer cells. Ad-FZ33 expressing LacZ combined with antibodies against EpCAM or EGFR, followed by β-gal assay, demonstrated highly efficient gene transduction in these biliary cancer cells, compared to the treatment with control antibody or without antibody. Ad-FZ33 expressing uracil phosphoribosyl transferase (UPRT), an enzyme which greatly enhances the toxicity of 5-fluorouracil (FU), combined with antibodies against EpCAM or EGFR, remarkably enhanced the sensitivity of biliary cancer cells to 5-FU. By contrast, the treatment did not affect the 5-FU sensitivity of the cells not expressing EpCAM or EGFR including normal hepatocytes. Finally, treatments with the UPRT-expressing Ad-FZ33 with antibodies against EpCAM or EGFR, followed by 5-FU administration, significantly suppressed the growth of biliary cancer xenografts in nude mice. These results indicate that the gene therapy mediated by the Z33 fiber modified Ad with anti-EpCAM or anti-EGFR antibodies offers a potentially effective therapeutic modality against biliary cancers.
References
- 1 Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol 2003; 4: 167–76.
- 2 Schauer RJ, Meyer G, Baretton G, Schildberg FW, Rau HG. Prognostic factors and long-term results after surgery for gallbladder carcinoma: a retrospective study of 127 patients. Langenbeck Arch Surg 2001; 386: 110–7.
- 3
Henson DE, Saavedra JA, Corle D.
Carcinoma of the extrahepatic bile duct.
Cancer
1992;
70:
1498–1501.
10.1002/1097-0142(19920915)70:6<1498::AID-CNCR2820700609>3.0.CO;2-C CAS PubMed Web of Science® Google Scholar
- 4 Fukuda K, Abei M, Ugai H, Seo E, Wakayama M, Murata T, Todoroki T, Tanaka N, Hamada H, Yokoyama KK. E1A, E1B double-restricted oncolytic adenovirus for gene therapy of gallbladder cancer. Cancer Res 2003; 63: 4434–40.
- 5 Seo E, Abei M, Wakayama M, Fukuda K, Ugai H, Murata T, Todoroki T, Matsuzaki Y, Tanaka N, Hamada H, Yokoyama KK. Effective gene therapy for biliary tract cancer by a conditionally replicative adenovirus carrying uracil phosphoribosyltransferase (UPRT) gene: significance of timing of 5-fluorouracil administration. Cancer Res 2005; 65: 546–52.
- 6 Wakayama M, Abei M, Seo E, Kawashima R, Fukuda K, Ugai H, Murata T, Tanaka N, Hyodo I, Hamada H, Yokoyama KK. E1A, E1B double-restricted adenovirus with RGD-fiber modification exhibits enhanced oncolysis for CAR-deficient biliary cancers. Clin Cancer Res 2007; 13: 3043–50.
- 7 Fukuda K, Abei M, Kawashima R, Ugai H, Seo E, Wakayama M, Murata T, Endo S, Hamada H, Hyodo I, Yokoyama KK. E1A, E1B-double restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer. Cancer Gene Ther 2009; 16: 126–36.
- 8 Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW. Isolation of a common receptor for coxsachie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320–23.
- 9 Wickham TJ, Mathias P, Cheresh DA, Nemerow GR. Integrins a versus b3 and a versus b5 promote adenoviruses internalization but not virus attachment. Cell 1993; 73: 309–19.
- 10 Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowsky AI, Tseng CP, Wang Z, Hsieh JT. Loss of adenovirus receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res 1999; 5: 2571–79.
- 11 Krasnykh V, Dmitriev I, Navarro JG, Belousova N, Kashentseva E, Xiang J, Douglas JT, Curiel DT. Advanced generation adenoviral vectors possess augmented gene transfer efficiency based upon coxsachie adenovirus receptor-independent cellular entry capacity. Cancer Res 2000; 60: 6784–87.
- 12 Barnett BG, Crews CJ, Douglas JT. Targeted adenoviral vectors. Biochim Biophys Acta 2002; 1575: 1–14.
- 13 Young LS, Searle PF, Onion D, Mautner V. Viral gene therapy strategies: from basic science to clinical application. J Pathol 2006; 208: 299–318.
- 14 Campos SK, Barry MA. Current advances and future challenges in adenoviral vector biology and targeting. Curr Gene Ther 2007; 7: 189–204.
- 15 Volpers C, Thirion C, Biermann V, Hussmann S, Kewes H, Dunant P, von der Mark H, Herrmann A, Kochanek S, Lochmüller H. Antibody-mediated targeting of an adenovirus vector modified to contain a synthetic immunoglobulin G-binding domain in the capsid. J Virol 2003; 77: 2093–2104.
- 16 Korokhov N, Mikheeva G, Krendelshchikov A, Belousova N, Simonenko V, Krendelshchikova V, Pereboev A, Kotov A, Kotova O, Triozzi PL, Aldrich WA, Douglas JT, et al. Targeting of adenovirus via genetic modification of the viral capsid combined with a protein bridge. J Virol 2003; 77: 12931–40.
- 17 Tanaka T, Huang J, Hirai S, Kuroki M, Kuroki M, Watanabe N, Tomihara K, Kato K, Hamada H. Carcinoembryonic antigen-targeted selective gene therapy for gastric cancer through FZ33 fiber-modified adenovirus vectors. Clin Cancer Res 2006; 12: 3803–13.
- 18 Pinedo HM, Peters GFJ. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6: 1653–64.
- 19 Kanai F, Kawakami T, Hamada H, Sadata A, Yoshida Y, Tanaka T, Ohashi M, Tateishi K, Shiratori Y, Omata M. Adenovirus-mediated transduction of Escheria coli uracil phosphoribosyltransferase gene sencitizes cancer cells to low concentration of 5-fluorouracil. Cancer Res 1998; 58: 1946–51.
- 20 Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO. EpCAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 1994; 125: 437–46.
- 21 Münz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 2004; 23: 5748–58.
- 22 Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 2004; 64: 5818–24.
- 23 Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S. Frequent EpCAM protein expression in human carcinomas. Human Pathol 2004; 35: 122–28.
- 24 Varga M, Obrist P, Schneeberger S, Muhlmann G, Farnholz FC, Fong D, Zitt M, Brunhuber T, Schäfer G, Gastl G, Spizzo G. Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clin Cancer Res 2004; 10: 3131–36.
- 25 Prince S, Zeidman A, Dekel Y, Ram E, Koren R. Expression of epithelial cell adhesion molecule in gallbladder carcinoma and its correlation with clinicopathologic variables. Am J Clin Pathol 2008; 129: 424–29.
- 26 Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5: 341–54.
- 27 Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005; 23: 2445–59.
- 28 Lee CS, Pirdas A. Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumors. Pathol Res Pract 1995; 191: 1087–91.
- 29 Altimari A, Fiorentino M, Gabusi E, Gruppioni E, Corti B, D'Errico A, Grigioni WF. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours. Dig Liver Dis 2003; 35: 332–8.
- 30 Yoon JH, Gwak GY, Lee HS, Bronk SF, Werneburg NW, Gores GJ. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol 2004; 41: 808–14.
- 31 Kaufman M, Mehrotra B, Limaye S, White S, Fuchs A, Lebowicz Y, Nissel-Horowitz S, Thomas A. EGFR expression in gallbladder carcinoma in North America. Int J Med Sci 2008; 5: 285–91.
- 32 Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W, Venesio T, Capussotti L, Risio M, Aglietta M. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 2006; 12: 1680–85.
- 33 Ito Y, Takeda T, Sasaki Y, Sakon M, Yamada T, Ishiguro S, Imaoka S, Tsujimoto M, Higashiyama S, Monden M, Matsuura N. Expression and clinical significance of the ErbB family in intrahepatic cholangiocellular carcinoma. Pathol Res Pract 2001; 197: 95–100.
- 34 Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 2005; 206: 356–65.
- 35 Kawamoto T, Krishnamurthy S, Tarco E, Trivedi S, Wistuba II, Li D, Roa I, Roa JC, Thomas MB. HER receptor family: novel candidate for targeted therapy for gallbladder and extrahepatic bile duct cancer. Gastrointest Cancer Res 2007; 6: 221–27.
- 36 Agrawal S, Kuvshinoff BW, Khoury T, Yu J, Javle MM, LeVea C, Groth J, Coignet LJ, Gibbs JF. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg 2007; 11: 445–451.
- 37 Choi Y-L, Xuan YH, Shin YK, Chae SW, Kook MC, Sung RH, Youn SJ, Choi JW, Kim SH. An immunohistochemical study of the expression of adhesion molecules in gallbladder lesions. J Histochem Cytochem 2004; 52: 591–601.
- 38 Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 2006; 24: 3069–74.
- 39 Paule B, Herelle MO, Rage E, Ducreux M, Adam R, Guettier C, Bralet MP. Cetuximab plus gemcitabin-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology 2007; 72: 105–10.
- 40 Wickham TJ, Roelvink PW, Brough DE, Kovesdi I. Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types. Nat Biotech 1996; 14: 1570–73.
- 41 Shinoura N, Yoshida Y, Tsunoda R, Ohashi M, Zhang W, Asai A, Kirino T, Hamada H. Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for gene therapy of gliomas. Cancer Res 1999; 59: 3411–16.
- 42 Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G, Belousova N, Curiel DT. An adenovirus vector with genetrically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent mechanism. J Virol 1998; 75: 9706–13.
- 43 Wickham TJ, Segal D, Roelvink PW, Carrion ME, Lizonova A, Lee GM, Kovesdi I. Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J Virol 1996; 70: 6831–38.
- 44 Haisma HJ, Pinedo HM, van Rijswijk A, van der Muileman IM, Sosnowski BA, Ying W, Beusechem VW, Tillman BW, Gerritsen WR, Curiel DT. Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM. Gene Ther 1999; 6: 1469–1474.
- 45 Heideman DAM, Snijders PJF, Craanen ME, Bloemena E, Meijer CJLM, Meuwissen SGM, van Beusechem VW, Pinedo HM, Curiel DT, Haisma HJ, Gerritsen WR. Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenovirus vectors. Cancer Gene Ther 2001; 8: 342–51.
- 46 Watkins SJ, Mesyanzhinov VV, Kurochkina LP, Hawkins RE. The adenobody approach to viral targeting: specific and enhanced adenoviral gene delivery. Gene Ther 1997; 4: 1004–12.
- 47 Dmitriev I, Kashentseva E, Rogers BE, Krasnykh V, Curiel DT. Ectodomain of coxachievirus and adenovirus receptor genetically fused to epidermal growth factor mediates adenovirus targeting to epidermal growth factor receptor-positive cells. J Virol 2000; 74: 6875–84.
- 48 Miller CR, Bushsbaum DJ, Reynolds PN, Douglas JT, Gillespie GY, Mayo MS, Raben D, Curiel DT. Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer. Cancer Res 1998; 58: 5738–48.
- 49 Haisma HJ, Grill J, Curiel DT, Hoogeland S, van Beusechem VW, Pinedo HM, Gerritsen WR. Targeting of adenoviral vectors through a bispecific single-chain antibody. Cancer Gene Ther 2000; 7: 901–4.
- 50 O'Riordan CR, Song A. PEGylated adenovirus for targeted gene therapy. Methods Mol Biol 2008; 434: 133–60.
Citing Literature
