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Published in: Clinical and Translational Oncology 5/2016

01-05-2016 | Research Article

The combinational therapy of trastuzumab and cetuximab inhibits tumor growth in a patient-derived tumor xenograft model of gastric cancer

Authors: C. J. Wang, P. J. Tong, M. Y. Zhu

Published in: Clinical and Translational Oncology | Issue 5/2016

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Abstract

Purpose

Gastric cancer (GC) is one of the leading causes of cancer mortality worldwide. Although therapeutic strategies for GC have improved, the prognosis for advanced GC remains poor. Herein, the present study sought to design a personalized cancer therapy specific to a stage III GC patient.

Methods

The tumor was surgically removed and was used to establish a patient-derived tumor xenograft (PDTX) model utilizing nude mice. Various molecular-targeted anticancer treatments were tested in the study, including control (no treatment), bevacizumab, cetuximab, bevacizumab + cetuximab, trastuzumab, and trastuzumab + cetuximab.

Results

Trastuzumab + cetuximab treatment exhibited the best antitumor growth effect, followed by trastuzumab, bevacizumab + cetuximab, cetuximab, and bevacizumab. Similarly, trastuzumab + cetuximab was also the most effective treatment at inducing apoptosis and cell cycle arrest in primary cultures of the patient’s gastric cancer cells. Among all treatments tested in the study, trastuzumab + cetuximab showed the most profound effect in reducing the protein expression of proliferation and metastatic markers (VEGF, MMP-7, EGFT, Ki-67 and, PCNA) in tumors obtained from PDTX models, which may be the mechanism underlying the profound antitumor growth effect exerted by trastuzumab + cetuximab.

Conclusions

The data indicate that trastuzumab + cetuximab combinational therapy should be the most effective antitumor growth therapy for the GC patient whom we took the cancer cells from.
Literature
2.
go back to reference Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97. doi:10.1016/S0140-6736(10)61121-X.CrossRefPubMed Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97. doi:10.​1016/​S0140-6736(10)61121-X.CrossRefPubMed
3.
go back to reference Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(26):3219–25. doi:10.1200/JCO.2013.48.8585.CrossRef Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(26):3219–25. doi:10.​1200/​JCO.​2013.​48.​8585.CrossRef
4.
go back to reference Koukourakis GV, Sotiropoulou-Lontou A. Targeted therapy with bevacizumab (Avastin) for metastatic colorectal cancer. Clin Transl Oncol Off Publ Fed Spanish Oncol Soc Natl Cancer Inst Mexico. 2011;13(10):710–4. doi:10.1007/s12094-011-0720-z. Koukourakis GV, Sotiropoulou-Lontou A. Targeted therapy with bevacizumab (Avastin) for metastatic colorectal cancer. Clin Transl Oncol Off Publ Fed Spanish Oncol Soc Natl Cancer Inst Mexico. 2011;13(10):710–4. doi:10.​1007/​s12094-011-0720-z.
5.
go back to reference Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50. doi:10.1056/NEJMoa061884.CrossRefPubMed Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50. doi:10.​1056/​NEJMoa061884.CrossRefPubMed
6.
go back to reference Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1252–60. doi:10.1200/JCO.2010.28.0982.CrossRef Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1252–60. doi:10.​1200/​JCO.​2010.​28.​0982.CrossRef
8.
go back to reference Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11. doi:10.1016/S0140-6736(07)61904-7.CrossRefPubMed Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11. doi:10.​1016/​S0140-6736(07)61904-7.CrossRefPubMed
9.
12.
go back to reference Pinto C, Di Fabio F, Barone C, Siena S, Falcone A, Cascinu S, et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer. 2009;101(8):1261–8. doi:10.1038/sj.bjc.6605319.CrossRefPubMedPubMedCentral Pinto C, Di Fabio F, Barone C, Siena S, Falcone A, Cascinu S, et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer. 2009;101(8):1261–8. doi:10.​1038/​sj.​bjc.​6605319.CrossRefPubMedPubMedCentral
13.
go back to reference Lordick F, Luber B, Lorenzen S, Hegewisch-Becker S, Folprecht G, Woll E, et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer. 2010;102(3):500–5. doi:10.1038/sj.bjc.6605521.CrossRefPubMedPubMedCentral Lordick F, Luber B, Lorenzen S, Hegewisch-Becker S, Folprecht G, Woll E, et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer. 2010;102(3):500–5. doi:10.​1038/​sj.​bjc.​6605521.CrossRefPubMedPubMedCentral
14.
go back to reference Long ZW, Wang JL, Wang YN. Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(11):11415–26. doi:10.1007/s13277-014-2441-8.CrossRef Long ZW, Wang JL, Wang YN. Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(11):11415–26. doi:10.​1007/​s13277-014-2441-8.CrossRef
16.
go back to reference Czyzewska J, Guzinska-Ustymowicz K, Lebelt A, Zalewski B, Kemona A. Evaluation of proliferating markers Ki-67, PCNA in gastric cancers. Rocz Akad Med Bialymst. 2004;49(Suppl 1):64–6.PubMed Czyzewska J, Guzinska-Ustymowicz K, Lebelt A, Zalewski B, Kemona A. Evaluation of proliferating markers Ki-67, PCNA in gastric cancers. Rocz Akad Med Bialymst. 2004;49(Suppl 1):64–6.PubMed
17.
go back to reference Terada R, Yasutake T, Nakamura S, Hisamatsu T, Nakagoe T, Ayabe H, et al. Evaluation of metastatic potential of gastric tumors by staining for proliferating cell nuclear antigen and chromosome 17 numerical aberrations. Ann Surg Oncol. 2001;8(6):525–32.CrossRefPubMed Terada R, Yasutake T, Nakamura S, Hisamatsu T, Nakagoe T, Ayabe H, et al. Evaluation of metastatic potential of gastric tumors by staining for proliferating cell nuclear antigen and chromosome 17 numerical aberrations. Ann Surg Oncol. 2001;8(6):525–32.CrossRefPubMed
21.
go back to reference Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, et al. Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(20):6456–68. doi:10.1158/1078-0432.CCR-08-0138.CrossRef Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, et al. Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(20):6456–68. doi:10.​1158/​1078-0432.​CCR-08-0138.CrossRef
22.
go back to reference Rubio-Viqueira B, Jimeno A, Cusatis G, Zhang X, Iacobuzio-Donahue C, Karikari C, et al. An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(15):4652–61. doi:10.1158/1078-0432.CCR-06-0113.CrossRef Rubio-Viqueira B, Jimeno A, Cusatis G, Zhang X, Iacobuzio-Donahue C, Karikari C, et al. An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(15):4652–61. doi:10.​1158/​1078-0432.​CCR-06-0113.CrossRef
23.
go back to reference Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(13):3989–98. doi:10.1158/1078-0432.CCR-07-0078.CrossRef Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(13):3989–98. doi:10.​1158/​1078-0432.​CCR-07-0078.CrossRef
26.
go back to reference Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: fifth edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis. Cancer. 2000;88(4):921–32.CrossRefPubMed Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: fifth edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis. Cancer. 2000;88(4):921–32.CrossRefPubMed
27.
go back to reference Wanebo HJ, Kennedy BJ, Chmiel J, Steele G Jr, Winchester D, Osteen R. Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg. 1993;218(5):583–92.CrossRefPubMedPubMedCentral Wanebo HJ, Kennedy BJ, Chmiel J, Steele G Jr, Winchester D, Osteen R. Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg. 1993;218(5):583–92.CrossRefPubMedPubMedCentral
28.
go back to reference Ryu KH, Shim KN, Jung SA, Yoo K, Joo YH, Lee JH. Significance of preoperative tissue levels of vascular-endothelial cadherin, liver–intestine cadherin and vascular endothelial growth factor in gastric cancer. Korean J Gastroenterol Taehan Sohwagi Hakhoe chi. 2012;60(4):229–41.CrossRefPubMed Ryu KH, Shim KN, Jung SA, Yoo K, Joo YH, Lee JH. Significance of preoperative tissue levels of vascular-endothelial cadherin, liver–intestine cadherin and vascular endothelial growth factor in gastric cancer. Korean J Gastroenterol Taehan Sohwagi Hakhoe chi. 2012;60(4):229–41.CrossRefPubMed
29.
go back to reference Liu L, Ma XL, Xiao ZL, Li M, Cheng SH, Wei YQ. Prognostic value of vascular endothelial growth factor expression in resected gastric cancer. Asian Pac J Cancer Prev APJCP. 2012;13(7):3089–97.CrossRefPubMed Liu L, Ma XL, Xiao ZL, Li M, Cheng SH, Wei YQ. Prognostic value of vascular endothelial growth factor expression in resected gastric cancer. Asian Pac J Cancer Prev APJCP. 2012;13(7):3089–97.CrossRefPubMed
31.
go back to reference Larbouret C, Robert B, Bascoul-Mollevi C, Penault-Llorca F, Ho-Pun-Cheung A, Morisseau S, et al. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2010;21(1):98–103. doi:10.1093/annonc/mdp496.CrossRef Larbouret C, Robert B, Bascoul-Mollevi C, Penault-Llorca F, Ho-Pun-Cheung A, Morisseau S, et al. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2010;21(1):98–103. doi:10.​1093/​annonc/​mdp496.CrossRef
32.
go back to reference Zheng L, Tan W, Zhang J, Yuan D, Yang J, Liu H. Combining trastuzumab and cetuximab combats trastuzumab-resistant gastric cancer by effective inhibition of EGFR/ErbB2 heterodimerization and signaling. Cancer Immunol Immunother CII. 2014;63(6):581–6. doi:10.1007/s00262-014-1541-z.CrossRefPubMed Zheng L, Tan W, Zhang J, Yuan D, Yang J, Liu H. Combining trastuzumab and cetuximab combats trastuzumab-resistant gastric cancer by effective inhibition of EGFR/ErbB2 heterodimerization and signaling. Cancer Immunol Immunother CII. 2014;63(6):581–6. doi:10.​1007/​s00262-014-1541-z.CrossRefPubMed
33.
go back to reference Wild R, Fager K, Flefleh C, Kan D, Inigo I, Castaneda S, et al. Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels. Mol Cancer Ther. 2006;5(1):104–13. doi:10.1158/1535-7163.MCT-05-0259.CrossRefPubMed Wild R, Fager K, Flefleh C, Kan D, Inigo I, Castaneda S, et al. Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels. Mol Cancer Ther. 2006;5(1):104–13. doi:10.​1158/​1535-7163.​MCT-05-0259.CrossRefPubMed
Metadata
Title
The combinational therapy of trastuzumab and cetuximab inhibits tumor growth in a patient-derived tumor xenograft model of gastric cancer
Authors
C. J. Wang
P. J. Tong
M. Y. Zhu
Publication date
01-05-2016
Publisher
Springer Milan
Published in
Clinical and Translational Oncology / Issue 5/2016
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-015-1397-5

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