Targeted therapy for gastric cancer: Current status and future directions (Review)

Yuan,Dan-Dan; Zhu,Zhong-Xiu; Zhang,Xia; Liu,Jie

doi:10.3892/or.2015.4528

Targeted therapy for gastric cancer: Current status and future directions (Review)

Authors:
- Dan-Dan Yuan
- Zhong-Xiu Zhu
- Xia Zhang
- Jie Liu
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Affiliations: Department of Internal Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China, Department of Internal Oncology Ward 7, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
Published online on: December 29, 2015 https://doi.org/10.3892/or.2015.4528
Pages: 1245-1254

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Abstract

According to the 2012 statistics of the International Agency for Research on Cancer (IARC), gastric cancer is the fifth most common malignancy, and the third leading cause of cancer-related deaths worldwide. Conventional chemotherapy and radiation have shown limited efficacy for advanced gastric cancer, showing an overall survival (OS) rate of ~10 months. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is the first approved molecularly targeted agent for HER2-overexpressing gastric cancer, which was found to prolong the OS and the progression-free survival (PFS) of patients. However, HER2 overexpression is present only in a minority of patients with gastric cancer. Hence, other targeted agents are urgently needed. Ramucirumab, a novel human IgG1 monoclonal antibody that selectively targets the extracellular domain of VEGF receptor 2 (VEGFR2), is regarded as a new standard second-line treatment for patients with advanced gastric cancer. The combination of two or more targeted agents directed against two different molecular targets may improve the survival of patients with advanced gastric cancer. Although great efforts have been made, the effect of targeted therapy for gastric cancer is limited. One key reason is that participants in clinical trials for new targeted agents were not selected by detection of the targeted molecule. Here, we review clinical trials related to molecular targets such as anti-epidermal growth factor receptor signaling including anti-HER2 and anti-EGFR1, anti-VEGF signaling, anti-mammalian target of rapamycin (mTOR), tyrosine kinase inhibitors (TKIs) and anti-MET.

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1	Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
2	Schlessinger J: Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 110:669–672. 2002. View Article : Google Scholar : PubMed/NCBI
3	Riese DJ II and Stern DF: Specificity within the EGF family/ErbB receptor family signaling network. BioEssays. 20:41–48. 1998. View Article : Google Scholar : PubMed/NCBI
4	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
5	Tang J, Liu N and Zhuang S: Role of epidermal growth factor receptor in acute and chronic kidney injury. Kidney Int. 83:804–810. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kim MA, Lee HS, Lee HE, Jeon YK, Yang HK and Kim WH: EGFR in gastric carcinomas: Prognostic significance of protein overexpression and high gene copy number. Histopathology. 52:738–746. 2008. View Article : Google Scholar : PubMed/NCBI
7	Langer R, Von Rahden BH, Nahrig J, Von Weyhern C, Reiter R, Feith M, Stein HJ, Siewert JR, Höfler H and Sarbia M: Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: A tissue microarray study. J Clin Pathol. 59:631–634. 2006. View Article : Google Scholar : PubMed/NCBI
8	Lieto E, Ferraraccio F, Orditura M, Castellano P, Mura AL, Pinto M, Zamboli A, De Vita F and Galizia G: Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 15:69–79. 2008. View Article : Google Scholar
9	Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al ToGA Trial Investigators: 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. 376:687–697. 2010. View Article : Google Scholar : PubMed/NCBI
10	Ryu MH, Yoo C, Kim JG, Ryoo BY, Park YS, Park SR, Han HS, Chung IJ, Song EK, Lee KH, et al: Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer. 51:482–488. 2015. View Article : Google Scholar : PubMed/NCBI
11	Chua C, Tan IB, Yamada Y, Rha SY, Yong WP, Ong WS, Tham CK, Ng M, Tai DW, Iwasa S, et al: Phase II study of trastuzumab in combination with S-1 and cisplatin in the first-line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol. 76:397–408. 2015. View Article : Google Scholar : PubMed/NCBI
12	Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar : PubMed/NCBI
13	Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol. 14:481–489. 2013. View Article : Google Scholar : PubMed/NCBI
14	Zhang X, Xu J, Liu H, Yang L, Liang J, Xu N, Bai Y, Wang J and Shen L: Predictive biomarkers for the efficacy of cetuximab combined with cisplatin and capecitabine in advanced gastric or esophagogastric junction adenocarcinoma: A prospective multi-center phase 2 trial. Med Oncol. 31:2262014. View Article : Google Scholar
15	Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, et al Arbeitsgemeinschaft Internistische Onkologie and EXPAND Investigators: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 14:490–499. 2013. View Article : Google Scholar : PubMed/NCBI
16	Xu CD: Clinical study of nimotuzumab combined with chemotherapy in the treatment of late stage gastric cancer. Asian Pac J Cancer Prev. 15:10273–10276. 2014. View Article : Google Scholar
17	Gupta MK and Qin RY: Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol. 9:1144–1155. 2003. View Article : Google Scholar : PubMed/NCBI
18	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS and Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 362:841–844. 1993. View Article : Google Scholar : PubMed/NCBI
20	Ferrara N, Hillan KJ, Gerber HP and Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 3:391–400. 2004. View Article : Google Scholar : PubMed/NCBI
21	Uronis HE, Bendell JC, Altomare I, Blobe GC, Hsu SD, Morse MA, Pang H, Zafar SY, Conkling P, Favaro J, et al: A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. Oncologist. 18:271–272. 2013. View Article : Google Scholar : PubMed/NCBI
22	Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 29:3968–3976. 2011. View Article : Google Scholar : PubMed/NCBI
23	Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, Peng Yong W, Langer B, Delmar P, Scherer SJ, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 30:2119–2127. 2012. View Article : Google Scholar : PubMed/NCBI
24	Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, et al: Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: Randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 18:168–176. 2015. View Article : Google Scholar :
25	Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQ, Serkova NJ, et al: Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 28:780–787. 2010. View Article : Google Scholar : PubMed/NCBI
26	Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, et al REGARD Trial Investigators: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 383:31–39. 2014. View Article : Google Scholar
27	Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, et al RAINBOW Study Group: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 15:1224–1235. 2014. View Article : Google Scholar : PubMed/NCBI
28	Yoon HH, Bendell JC, Braiteh FS, Firdaus I, Philip PA, Cohn AL, Lewis N, Anderson DM, Arrowsmith E, Schwartz JD, et al: Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial. J Clin Oncol. 32(Suppl 5s): 40042014.
29	Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, Ayoub J, Lago S, de Albuquerque Ribeiro R, Gerogianni A, et al National Cancer Institute of Canada Clinical Trials Group Study BR.21: Symptom improvement in lung cancer patients treated with erlotinib: Quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 24:3831–3837. 2006. View Article : Google Scholar : PubMed/NCBI
30	Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al National Cancer Institute of Canada Clinical Trials Group: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 353:123–132. 2005. View Article : Google Scholar : PubMed/NCBI
31	Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 356:115–124. 2007. View Article : Google Scholar : PubMed/NCBI
32	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
33	Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar
34	Martin-Richard M, Gallego R, Pericay C, Garcia Foncillas J, Queralt B, Casado E, Barriuso J, Iranzo V, Juez I, Visa L, et al: Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study. Invest New Drugs. 31:1573–1579. 2013. View Article : Google Scholar : PubMed/NCBI
35	Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH and Benson AB III: Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol. 28:2947–2951. 2010. View Article : Google Scholar : PubMed/NCBI
36	Bang YJ, Kang YK, Kang WK, Boku N, Chung HC, Chen JS, Doi T, Sun Y, Shen L, Qin S, et al: Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs. 29:1449–1458. 2011. View Article : Google Scholar :
37	Boku N, Muro K, Machida N, Hashigaki S, Kimura N, Suzuki M, Lechuga M and Miyata Y: Phase I study of sunitinib plus S-1 and cisplatin in Japanese patients with advanced or metastatic gastric cancer. Invest New Drugs. 32:261–270. 2014. View Article : Google Scholar :
38	Lee KW, Park SR, Oh DY, Park YI, Khosravan R, Lin X, Lee SY, Roh EJ, Valota O, Lechuga MJ, et al: Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer. Invest New Drugs. 31:1547–1558. 2013. View Article : Google Scholar : PubMed/NCBI
39	Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, et al: Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: Results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol. 31:3219–3225. 2013. View Article : Google Scholar : PubMed/NCBI
40	Qin Sk; PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China: Phrase III study of apatinib in advanced gastric cancer: A randomized double-blind, placebo-controlled trial. J Clin Oncol. 32(Suppl 5s): 40032014.
41	Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, et al: Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN - a randomized, phase III study. J Clin Oncol. 32:2039–2049. 2014. View Article : Google Scholar : PubMed/NCBI
42	A Phase III study of ERBB2 positive advanced or metastatic gastric or esophageal or gastroesophageal junction adenocarcinoma treated with capecitabine plus oxaliplatin with or without lapatinib. J Clin Oncol. 31(Suppl): LBA40012013.
43	Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, et al: Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 117:376–380. 2005. View Article : Google Scholar : PubMed/NCBI
44	Lang SA, Gaumann A, Koehl GE, Seidel U, Bataille F, Klein D, Ellis LM, Bolder U, Hofstaedter F, Schlitt HJ, et al: Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer. 120:1803–1810. 2007. View Article : Google Scholar : PubMed/NCBI
45	Xu DZ, Geng QR, Tian Y, Cai MY, Fang XJ, Zhan YQ, Zhou ZW, Li W, Chen YB, Sun XW, et al: Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. BMC Cancer. 10:5362010. View Article : Google Scholar : PubMed/NCBI
46	Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, Jia Z, Li Q, Yao JC and Xie K: Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer. Clin Cancer Res. 15:1821–1829. 2009. View Article : Google Scholar : PubMed/NCBI
47	An JY, Kim KM, Choi MG, Noh JH, Sohn TS, Bae JM and Kim S: Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer. 126:2904–2913. 2010.
48	Wan X and Helman LJ: The biology behind mTOR inhibition in sarcoma. Oncologist. 12:1007–1018. 2007. View Article : Google Scholar : PubMed/NCBI
49	Lim T, Lee J, Lee DJ, Lee HY, Han B, Baek KK, Ahn HK, Lee SJ, Park SH, Park JO, et al: Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. Cancer Chemother Pharmacol. 68:255–262. 2011. View Article : Google Scholar : PubMed/NCBI
50	Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, Komatsu Y, Hamamoto Y, Ohno N, Fujita Y, et al: Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol. 28:1904–1910. 2010. View Article : Google Scholar : PubMed/NCBI
51	Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, et al: Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 31:13935–13943. 2013. View Article : Google Scholar
52	Slørdahl TS, Denayer T, Moen SH, Standal T, Børset M, Ververken C and Rø TB: Anti-c-MET nanobody - a new potential drug in multiple myeloma treatment. Eur J Haematol. 91:399–410. 2013. View Article : Google Scholar : PubMed/NCBI
53	Stellrecht CM and Gandhi V: MET receptor tyrosine kinase as a therapeutic anticancer target. Cancer Lett. 280:1–14. 2009. View Article : Google Scholar
54	Sotoudeh K, Hashemi F, Madjd Z, Sadeghipour A, Molanaei S and Kalantary E: The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays. Diagn Pathol. 7:572012. View Article : Google Scholar : PubMed/NCBI
55	Ha SY, Lee J, Kang SY, Do IG, Ahn S, Park JO, Kang WK, Choi MG, Sohn TS, Bae JM, et al: MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas. Mod Pathol. 26:1632–1641. 2013. View Article : Google Scholar : PubMed/NCBI
56	Fuse N, Kuboki Y, Kuwata T, Nishina T, Kadowaki S, Shinozaki E, Machida N, Yuki S, Ooki A, Kajiura S, et al: Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer. Feb 15–2015.Epub ahead of print. PubMed/NCBI
57	Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, et al: Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: An open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 15:1007–1018. 2014. View Article : Google Scholar : PubMed/NCBI
58	Shah MA, Cho JY, Huat ITB, Tebbutt NC, Yen CJ, Kang A, Shames DS, Bu L and Kang YK: Randomized phase II study of FOLFOX/- MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC). J Clin Oncol. 33:abstract 2. 2015.
59	Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim YH, Park JO, Chun HG, Zang DY, et al: Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 33:3858–3865. 2015. View Article : Google Scholar : PubMed/NCBI
60	Malenfant SJ, Eckmann KR and Barnett CM: Pertuzumab: A new targeted therapy for HER2-positive metastatic breast cancer. Pharmacotherapy. 34:60–71. 2014. View Article : Google Scholar
61	Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, et al CLEOPATRA Study Group: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 366:109–119. 2012. View Article : Google Scholar
62	Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, et al CLEOPATRA Study Group: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 372:724–734. 2015. View Article : Google Scholar : PubMed/NCBI
63	Kang YK, Rha SY, Tassone P, Barriuso J, Yu R, Szado T, Garg A and Bang YJ: A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br J Cancer. 111:660–666. 2014. View Article : Google Scholar : PubMed/NCBI