Recent updates of precision therapy for gastric cancer: Towards optimal tailored management

World Journal of Gastroenterology

Volumn 22, Issue 19, 2016, Pages 4638-4650

  Joo, Moon Kyung ^a   Park, Jong Jae ^a   Chun, Hoon Jai ^a  

^a Korea University College of Medicine   (South Korea)

Author keywords

Gastric cancer; Hepatocyte growth factor; Mammalian target of rapamycin; Programmed cell death ligand 1; Signal transducer and activator of transcription 3

Indexed keywords

8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; ALPELISIB; CAPECITABINE; CISPLATIN; EPIRUBICIN; ERLOTINIB; EVEROLIMUS; FLUOROURACIL; FOLINIC ACID; JANUS KINASE 2; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; ONARTUZUMAB; OXALIPLATIN; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN KINASE B; PROTEIN SH2; RAPAMYCIN; REGORAFENIB; RILOTUMUMAB; SCATTER FACTOR; SCATTER FACTOR RECEPTOR; SORAFENIB; STAT3 PROTEIN; TIVANTINIB; UNINDEXED DRUG; ANTINEOPLASTIC AGENT; TUMOR MARKER;

ACCURACY; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; CANCER GROWTH; CANCER INHIBITION; CANCER PROGNOSIS; CANCER RESEARCH; CANCER STAGING; DRUG TARGETING; HUMAN; MONOTHERAPY; MULTICENTER STUDY (TOPIC); MUTATIONAL ANALYSIS; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS INHIBITION; REVIEW; SIGNAL TRANSDUCTION; STOMACH CANCER; STOMACH CARCINOGENESIS; TREATMENT FAILURE; TUMOR MICROENVIRONMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; DISEASE FREE SURVIVAL; DRUG EFFECTS; GENETIC POLYMORPHISM; GENETIC PREDISPOSITION; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY; MORTALITY; MUTATION; PATIENT SELECTION; PERSONALIZED MEDICINE; PHENOTYPE; PREDICTIVE VALUE; PROCEDURES; RISK FACTOR; STOMACH NEOPLASMS; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; DISEASE-FREE SURVIVAL; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MOLECULAR TARGETED THERAPY; MUTATION; PATIENT SELECTION; PHENOTYPE; POLYMORPHISM, GENETIC; PRECISION MEDICINE; PREDICTIVE VALUE OF TESTS; RISK FACTORS; SIGNAL TRANSDUCTION; STOMACH NEOPLASMS; TREATMENT OUTCOME;

EID: 84977655916     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v22.i19.4638     Document Type: Review

References (108)

1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24: 2137-2150 [PMID: 16682732 DOI:10.1200/JCO.2005.05.2308].
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202-209 [PMID: 25079317 DOI:10.1038/nature13480].
3. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK. 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: 687-697 [PMID: 20728210 DOI:10.1016/S0140-6736(10)61121-X].
4. Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric cancer-molecular and clinical dimensions. Nat Rev Clin Oncol 2013; 10: 643-655 [PMID: 24061039 DOI:10.1038/nrclinonc.2013.170].
5. Blumenschein GR, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012; 30: 3287-3296 [PMID: 22869872 DOI:10.1200/JCO.2011.40.3774].
6. Samamé Pérez-Vargas JC, Biondani P, Maggi C, Gariboldi M, Gloghini A, Inno A, Volpi CC, Gualeni AV, di Bartolomeo M, de Braud F, Castano A, Bossi I, Pietrantonio F. Role of cMET in the development and progression of colorectal cancer. Int J Mol Sci 2013; 14: 18056-18077 [PMID: 24005867 DOI:10.3390/ijms140918056].
7. Gu H, Neel BG. The "Gab" in signal transduction. Trends Cell Biol 2003; 13: 122-130 [PMID: 12628344].
8. Yu S, Yu Y, Zhao N, Cui J, Li W, Liu T. C-Met as a prognostic marker in gastric cancer: A systematic review and meta-analysis. Plos One 2013; 8: E79137 [PMID: 24223894 DOI:10.1371/journal.pone.0079137].
9. Peng Z, Li Z, Gao J, Lu M, Gong J, Tang ET, Oliner KS, Hei YJ, Zhou H, Shen L. Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer. Mol Cancer Ther 2015; 14: 2634-2641 [PMID: 26330547 DOI:10.1158/1535-7163.MCT-15-0108].
10. Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, Matsuda M, Sakaguchi T, Hirao T, Nakano H. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 1999; 85: 1894-1902 [PMID: 10223227].
11. Janjigian YY, Tang LH, Coit DG, Kelsen DP, Francone TD, Weiser MR, Jhanwar SC, Shah MA. MET expression and amplification in patients with localized gastric cancer. Cancer Epidemiol Biomarkers Prev 2011; 20: 1021-1027 [PMID: 21393565 DOI:10.1158/1055-9965.EPI-10-1080].
12. Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, Lauwers GY, Christensen JG, Wilner KD, Haber DA, Salgia R, Bang YJ, Clark JW, Solomon BJ, Iafrate AJ. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011; 29: 4803-4810 [PMID: 22042947 DOI:10.1200/JCO.2011.35.4928].
13. Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2015; 33: 2667-2674 [PMID: 26169611 DOI:10.1200/JCO.2014.60.7317].
14. Kang YK, Muro K, Ryu MH, Yasui H, Nishina T, Ryoo BY, Kamiya Y, Akinaga S, Boku N. A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or thirdline therapy in the patients with metastatic gastric cancer. Invest New Drugs 2014; 32: 355-361 [PMID: 24337769 DOI:10.1007/s10637-013-0057-2].
15. Matsuoka T, Yashiro M. The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma. Cancers (Basel) 2014; 6: 1441-1463 [PMID: 25003395 DOI:10.3390/cancers6031441].
16. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 129: 1261-1274 [PMID: 17604717 DOI:10.1016/j.cell.2007.06.009].
17. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554 [PMID: 15016963 DOI:10.1126/science.1096502].
18. Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005; 5: 29 [PMID: 15784156 DOI:10.1186/1471-2407-5-29].
19. Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 2005; 41: 1649-1654 [PMID: 15994075 DOI:10.1016/j.ejca.2005.04.022].
20. Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B, Hou P. Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer 2012; 12: 50 [PMID: 22292935 DOI:10.1186/1471-2407-12-50].
21. Tran TN, Brettingham-Moore K, Duong CP, Mitchell C, Clemons NJ, Phillips WA. Molecular changes in the phosphatidylinositide 3-kinase (PI3K) pathway are common in gastric cancer. J Surg Oncol 2013; 108: 113-120 [PMID: 23813545 DOI:10.1002/jso.23357].
22. Sukawa Y, Yamamoto H, Nosho K, Ito M, Igarashi H, Naito T, Mitsuhashi K, Matsunaga Y, Takahashi T, Mikami M, Adachi Y, Suzuki H, Shinomura Y. HER2 expression and PI3K-Akt pathway alterations in gastric cancer. Digestion 2014; 89: 12-17 [PMID: 24458107 DOI:10.1159/000356201].
23. Chong ML, Loh M, Thakkar B, Pang B, Iacopetta B, Soong R. Phosphatidylinositol-3-kinase pathway aberrations in gastric and colorectal cancer: meta-analysis, co-occurrence and ethnic variation. Int J Cancer 2014; 134: 1232-1238 [PMID: 23960014 DOI:10.1002/ijc.28444].
24. Mina S, Bohn BA, Simon R, Krohn A, Reeh M, Arnold D, Bokemeyer C, Sauter G, Izbicki JR, Marx A, Stahl PR. PTEN deletion is rare but often homogeneous in gastric cancer. J Clin Pathol 2012; 65: 693-698 [PMID: 22639407 DOI:10.1136/jclinpath-2011-200525].
25. Oki E, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Watanabe M, Ikebe M, Kakeji Y, Baba H, Maehara Y. Genetic mutual relationship between PTEN and p53 in gastric cancer. Cancer Lett 2005; 227: 33-38 [PMID: 16051030 DOI:10.1016/j.canlet.2004.12.006].
26. Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ, Chi SG. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer 2003; 104: 318-327 [PMID: 12569555 DOI:10.1002/ijc.10962].
27. Li YL, Tian Z, Wu DY, Fu BY, Xin Y. Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. World J Gastroenterol 2005; 11: 285-288 [PMID: 15633233 DOI:10.3748/wjg.v11.i2.285].
28. Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 2005; 117: 376-380 [PMID: 15900596 DOI:10.1002/ijc.21170].
29. Oki E, Kakeji Y, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Yamamoto M, Ikebe M, Maehara Y. Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer. J Gastroenterol Hepatol 2006; 21: 814-818 [PMID: 16704528 DOI:10.1111/j.1440-1746.2005.04028.x].
30. Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, Jia Z, Li Q, Yao JC, Xie K. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res 2009; 15: 1821-1829 [PMID: 19223493 DOI:10.1158/1078-0432.CCR-08-2138].
31. Li M, Sun H, Song L, Gao X, Chang W, Qin X. Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma. Oncol Lett 2012; 4: 1213-1218 [PMID: 23205120 DOI:10.3892/ol.2012.930].
32. ClinicalTrials.gov. PI3K Inhibitor BYL719 in Combination With the HSP90 Inhibitor AUY922 in Patients With Advanced or Metastatic Gastric Cancer. (accessed January 7, 2016). Available from: URL: http://www.clinicaltrials.gov/ct/show/NCT01613950.
33. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14: 736-746 [PMID: 25342631 DOI:10.1038/nrc3818].
34. Jackson CB, Giraud AS. STAT3 as a prognostic marker in human gastric cancer. J Gastroenterol Hepatol 2009; 24: 505-507 [PMID: 19368630 DOI:10.1111/j.1440-1746.2009.05822.x].
35. Giraud AS, Menheniott TR, Judd LM. Targeting STAT3 in gastric cancer. Expert Opin Ther Targets 2012; 16: 889-901 [PMID: 22834702 DOI:10.1517/14728222.2012.709238].
36. Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, Naka T, Ojima T, Ueda K, Hayata K, Nakamura Y, Yamaue H. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep 2011; 25: 1271-1277 [PMID: 21369705 DOI:10.3892/or.2011.1201].
37. Liu X, Jin H, Zhang G, Lin X, Chen C, Sun J, Zhang Y, Zhang Q, Yu J. Intratumor IL-17-positive mast cells are the major source of the IL-17 that is predictive of survival in gastric cancer patients. Plos One 2014; 9: E106834 [PMID: 25197971 DOI:10.1371/journal.pone.0106834].
38. Wu X, Yang T, Liu X, Guo JN, Xie T, Ding Y, Lin M, Yang H. IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer. Tumour Biol 2016; 37: 5493-5501 [PMID: 26566627 DOI:10.1007/s13277-015-4372].
39. Howlett M, Giraud AS, Lescesen H, Jackson CB, Kalantzis A, Van Driel IR, Robb L, Van der Hoek M, Ernst M, Minamoto T, Boussioutas A, Oshima H, Oshima M, Judd LM. The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. Gastroenterology 2009; 136: 967-977 [PMID: 19121317 DOI:10.1053/j.gastro.2008.12.003].
40. Han JC, Zhang KL, Chen XY, Jiang HF, Kong QY, Sun Y, Wu ML, Huang L, Li H, Liu J. Expression of seven gastric cancerassociated genes and its relevance for Wnt, NF-kappaB and Stat3 signaling. APMIS 2007; 115: 1331-1343 [PMID: 18184402 DOI:10.1111/j.1600-0643.2007.00695.x].
41. Rhee YH, Jeong SJ, Lee HJ, Lee HJ, Koh W, Jung JH, Kim SH, Sung-Hoon K. Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells. BMC Cancer 2012; 12: 28 [PMID: 22260501 DOI:10.1186/1471-2407-12-28].
42. Sandur SK, Pandey MK, Sung B, Aggarwal BB. 5-hydroxy-2- methyl-1, 4-naphthoquinone, a vitamin K3 analogue, suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase, SHP-1: potential role in chemosensitization. Mol Cancer Res 2010; 8: 107-118 [PMID: 20068065 DOI:10.1158/1541-7786.MCR-09-0257].
43. Lee JH, Chiang SY, Nam D, Chung WS, Lee J, Na YS, Sethi G, Ahn KS. Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases. Cancer Lett 2014; 345: 140-148 [PMID: 24333736 DOI:10.1016/j.canlet.2013.12.008].
44. Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 2010; 16: 5189-5199 [PMID: 20884624 DOI:10.1158/1078-0432.CCR-09-3389].
45. Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, Chen KF. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol 2011; 55: 1041-1048 [PMID: 21354226 DOI:10.1016/j.jhep.2011.01.047].
46. Chen KF, Tai WT, Hsu CY, Huang JW, Liu CY, Chen PJ, Kim I, Shiau CW. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem 2012; 55: 220-227 [PMID: 22871485 DOI:10.1016/j.ejmech.2012.07.023].
47. Tai WT, Shiau CW, Chen PJ, Chu PY, Huang HP, Liu CY, Huang JW, Chen KF. Discovery of novel Src homology region 2 domaincontaining phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology 2014; 59: 190-201 [PMID: 23908138 DOI:10.1002/hep.26640].
48. Huang CY, Tai WT, Hsieh CY, Hsu WM, Lai YJ, Chen LJ, Shiau CW, Chen KF. A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3. Cancer Lett 2014; 349: 136-143 [PMID: 24735751 DOI:10.1016/j.canlet.2014.04.006].
49. Fan LC, Shiau CW, Tai WT, Hung MH, Chu PY, Hsieh FS, Lin H, Yu HC, Chen KF. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene 2015; 34: 5252-5263 [PMID: 25619838 DOI:10.1038/onc.2014.445].
50. Su TH, Shiau CW, Jao P, Liu CH, Liu CJ, Tai WT, Jeng YM, Yang HC, Tseng TC, Huang HP, Cheng HR, Chen PJ, Chen KF, Kao JH, Chen DS. Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition. Proc Natl Acad Sci USA 2015; 112: 7243-7248 [PMID: 26039995 DOI:10.1073/pnas.1507499112].
51. Chao TI, Tai WT, Hung MH, Tsai MH, Chen MH, Chang MJ, Shiau CW, Chen KF. A combination of sorafenib and SC-43 is a synergistic SHP-1 agonist duo to advance hepatocellular carcinoma therapy. Cancer Lett 2016; 371: 205-213 [PMID: 26679051 DOI:10.1016/j.canlet.2015.11.039].
52. Joo MK, Park JJ, Yoo HS, Lee BJ, Chun HJ, Lee SW, Bak YT. Epigenetic regulation and anti-tumorigenic effects of SH2- containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells. Tumour Biol 2016; 37: 4603-4612 [PMID: 26508024 DOI:10.1007/s13277-015-4228-y].
53. Abdel-Rahman O. Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials. Crit Rev Oncol Hematol 2016; 97: 65-71 [PMID: 26321371 DOI:10.1016/j.critrevonc.2015.08.015].
54. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 2015; 125: 3384-3391 [PMID: 26325035 DOI:10.1172/JCI80011].
55. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006; 108: 19-24 [PMID: 16530813 DOI:10.1016/j.acthis.2006.01.003].
56. Lu B, Chen L, Liu L, Zhu Y, Wu C, Jiang J, Zhang X. T-cellmediated tumor immune surveillance and expression of B7 coinhibitory molecules in cancers of the upper gastrointestinal tract. Immunol Res 2011; 50: 269-275 [PMID: 21717068 DOI:10.1007/s12026-011-8227-9].
57. Hou J, Yu Z, Xiang R, Li C, Wang L, Chen S, Li Q, Chen M, Wang L. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Mol Pathol 2014; 96: 284-291 [PMID: 24657498 DOI:10.1016/j.yexmp.2014.03.005].
58. Qing Y, Li Q, Ren T, Xia W, Peng Y, Liu GL, Luo H, Yang YX, Dai XY, Zhou SF, Wang D. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther 2015; 9: 901-909 [PMID: 25733810 DOI:10.2147/DDDT.S75152].
59. Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. J Surg Oncol 2013; 107: 517-522 [PMID: 23129549 DOI:10.1002/jso.23281].
60. Kim JW, Nam KH, Ahn SH, Park do J, Kim HH, Kim SH, Chang H, Lee JO, Kim YJ, Lee HS, Kim JH, Bang SM, Lee JS, Lee KW. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer 2016; 19: 42-52 [PMID: 25424150 DOI:10.1007/s10120-014-0440-5].
61. Geng R, Dai C, Wong A, Qing M, Hu J, Sun Y, Lo AWI, Li J. Prognostic significance of tumor infiltrating immune cells and PD-L1 expression in gastric carcinoma in Chinese patients. J Clin Oncol 2015; 33 Suppl15: 4042.
62. Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, Nirni S, Lakshmaiah K, Thomas A, Jiang Y, Zhu M, Tang R, Anderson A, Dubey S, Oliner KS, Loh E. 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 doubleblind, randomised phase 2 study. Lancet Oncol 2014; 15: 1007-1018 [PMID: 24965569 DOI:10.1016/S1470-2045(14)70023-3].
63. Cunningham D, Tebbutt NC, Davidenko I, Murad AM, Al-Batran S-E, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe MA, Baker N, Oliner KS, Zhang Y, Hoang T, Sidhu R, Catenacci DVT. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced METpositive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol 2015; 33 Suppl15: 4000.
64. Doi T, Kang YK, Muro K, Jiang Y, Jain RK, Lizambri R. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial. J Clin Oncol 2015; 33 Suppl15: TPS226.
65. Shah MA, Bang YJ, Lordick F, Tabernero J, Chen M, Hack SP, Phan SC, Shames DS, Cunningham D. METGastric: A phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET ) adenocarcinoma of the stomach or gastroesophageal junction (GEC). J Clin Oncol 2015; 33 Suppl15: 4012.
66. Malka D, Castan F, Francois E, Bouche O, Bennouna J, Ghiringhelli F, Fouchardiere CDL, Borg C, Samalin E, Bachet JB, Raoul J-L, Cvitkovic F, Miglianico L, Bengrine-Lefevre L, Dahan L, Lecaille C, Aparicio T, Perrier H, Gourgou S, Taïeb J, Unicancer, (FFCD) FFdCD, (AGEO) AdG-EO. FOLFOX alone or combined to rilotumumab or panitumumab as first-line treatment in patients (pts) with advanced gastroesophageal adenocarcinoma (AGEA): An open-label, randomized phase II trial (PRODIGE 17 ACCORD 20 MEGA). J Clin Oncol 2015; 33 Suppl15: 4013.
67. Xu RH, Qiu M, Zhou YX, Wang DS, Zhang DS, Wang F, Li YH, Huang J, Zhou H, Tang ET, Du Z, Zhang F. Evaluation of tumor MET protein expression, MET gene amplification, and HER2 expression in Chinese patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer. J Clin Oncol 2015; 33 Suppl: Abstr 4048.
68. Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, Chandarlapaty S, Hamilton N, Gajria D, Knowles J, Shah J, Shannon K, Tetteh E, Sullivan DM, Moreno C, Yan L, Han HS. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2- positive solid tumors. Breast Cancer Res 2013; 15: R110 [PMID: 24252402 DOI:10.1186/bcr3577].
69. Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, Komatsu Y, Hamamoto Y, Ohno N, Fujita Y, Robson M, Ohtsu A. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 2010; 28: 1904-1910 [PMID: 20231677 DOI:10.1200/JCO.2009.26.2923].
70. Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013; 31: 3935-3943 [PMID: 24043745 DOI:10.1200/JCO.2012.48.3552].
71. Shen YC, Li CP, Yen CJ, Hsu C, Lin YL, Lin ZZ, Chen LT, Su WC, Chao Y, Yeh KH, Cheng AL. Phase II multicentered study of low-dose everolimus plus cisplatin and weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin as first-line treatment for patients with advanced gastric cancer. Oncology 2014; 87: 104-113 [PMID: 25011938 DOI:10.1159/000362671].
72. Park JH, Ryu MH, Park YS, Park SR, Na YS, Rhoo BY, Kang YK. Successful control of heavily pretreated metastatic gastric cancer with the mTOR inhibitor everolimus (RAD001) in a patient with PIK3CA mutation and pS6 overexpression. BMC Cancer 2015; 15: 119 [PMID: 25886409 DOI:10.1186/s12885-015-1139-7].
73. Wainberg ZA, Soares HP, Patel R, DiCarlo B, Park DJ, Liem A, Wang HJ, Yonemoto L, Martinez D, Laux I, Brennan M, Hecht JR. Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers. Cancer Chemother Pharmacol 2015; 76: 61-67 [PMID: 25969130 DOI:10.1007/s00280-015-2744-5].
74. Oh DY, Lee SH, Han SW, Kim MJ, Kim TM, Kim TY, Heo DS, Yuasa M, Yanagihara Y, Bang YJ. Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors. Cancer Res Treat 2015; 47: 607-615 [PMID: 25715763 DOI:10.4143/crt.2014.249].
75. Huang S, Chen M, Ding X, Zhang X, Zou X. Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway. Int Immunopharmacol 2013; 17: 585-592 [PMID: 23973653 DOI:10.1016/j.intimp.2013.07.021].
76. Pandey A, Vishnoi K, Mahata S, Tripathi SC, Misra SP, Misra V, Mehrotra R, Dwivedi M, Bharti AC. Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil. Nutr Cancer 2015; 67: 1293-1304 [PMID: 26492225 DOI:10.1080/01635581.2015.1085581].
77. Zhang B, Yang Y, Shi X, Liao W, Chen M, Cheng AS, Yan H, Fang C, Zhang S, Xu G, Shen S, Huang S, Chen G, Lv Y, Ling T, Zhang X, Wang L, Zhuge Y, Zou X. Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-β/β-catenin signaling and epithelialmesenchymal transition. Cancer Lett 2015; 356: 704-712 [PMID: 25449432 DOI:10.1016/j.canlet.2014.10.016].
78. Chen J, Wang J, Lin L, He L, Wu Y, Zhang L, Yi Z, Chen Y, Pang X, Liu M. Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther 2012; 11: 277-287 [PMID: 22203730 DOI:10.1158/1535-7163.MCT-11-0648].
79. Liu SH, Wang KB, Lan KH, Lee WJ, Pan HC, Wu SM, Peng YC, Chen YC, Shen CC, Cheng HC, Liao KK, Sheu ML. Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. Plos One 2012; 7: E43711 [PMID: 22937084 DOI:10.1371/journal.pone.0043711].
80. Zhu BH, Chen HY, Zhan WH, Wang CY, Cai SR, Wang Z, Zhang CH, He YL. (-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer. World J Gastroenterol 2011; 17: 2315-2325 [PMID: 21633597 DOI:10.3748/wjg.v17.i18.2315].
81. Huang S, Chen M, Shen Y, Shen W, Guo H, Gao Q, Zou X. Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. Cancer Lett 2012; 315: 198-205 [PMID: 22104727 DOI:10.1016/j.canlet.2011.10.011].
82. Gupta SC, Phromnoi K, Aggarwal BB. Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem Pharmacol 2013; 85: 898-912 [PMID: 23279849 DOI:10.1016/j.bcp.2012.12.018].
83. Ahn KS, Sethi G, Sung B, Goel A, Ralhan R, Aggarwal BB. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. Cancer Res 2008; 68: 4406-4415 [PMID: 18519703 DOI:10.1158/0008-5472.CAN-07-6696].
84. Prasad S, Pandey MK, Yadav VR, Aggarwal BB. Gambogic acid inhibits STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1: potential role in proliferation and apoptosis. Cancer Prev Res (Phila) 2011; 4: 1084-1094 [PMID: 21490133 DOI:10.1158/1940-6207.CAPR-10-0340].
85. Pandey MK, Sung B, Ahn KS, Aggarwal BB. Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1. Mol Pharmacol 2009; 75: 525-533 [PMID: 19103760 DOI:10.1124/mol.108.052548].
86. Rajendran P, Li F, Manu KA, Shanmugam MK, Loo SY, Kumar AP, Sethi G. γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent. Br J Pharmacol 2011; 163: 283-298 [PMID: 21198544 DOI:10.1111/j.1476-5381.2010.01187.x].
87. Tan SM, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G. Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther 2010; 334: 285-293 [PMID: 20378717 DOI:10.1124/jpet.110.165498].
88. Joo MK, Park JJ, Kim SH, Yoo HS, Lee BJ, Chun HJ, Lee SW, Bak YT. Antitumorigenic effect of plumbagin by induction of SH2- containing protein tyrosine phosphatase 1 in human gastric cancer cells. Int J Oncol 2015; 46: 2380-2388 [PMID: 25815436 DOI:10.3892/ijo.2015.2935].
89. Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, Hawkins RE, Thistlethwaite FC. Modulation of lymphocyte regulation for cancer therapy: A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res 2010; 16: 1662-1672 [PMID: 20179239 DOI:10.1158/1078-0432.CCR-09-2870].
90. Bang YJ, Chung HC, Shankaran V, Geva R, Catenacci DVT, Gupta S, Eder JP, Berger R, Gonzalez EJ, Ray A, Dolled-Filhart M, Emancipator K, Pathiraja K, Lunceford JK, Cheng JD, Minori Koshiji KM. Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in KEYNOTE-012. J Clin Oncol 2015; 33 Suppl15: 4001.
91. ClinicalTrials.gov. A Study of Pembrolizumab (MK-3475) in Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-059/KEYNOTE-059) (accessed January 4, 2016). Available from: URL: http://www.clinicaltrials.gov/ct/show/NCT02335411.
92. ClinicalTrials.gov. A Study of Pembrolizumab (MK-3475) Versus Paclitaxel for Participants With Advanced Gastric/Gastroesophageal Junction Adenocarcinoma That Progressed After Therapy With Platinum and Fluoropyrimidine (MK-3475-061/KEYNOTE-061) (accessed January 4, 2016). Available from: URL: http://www.clinicaltrials.gov/ct/show/NCT02370498.
93. Yamada Y, Nishina T, Iwasa S, Shitara K, Muro K, Esaki T, Hironaka S, Yamaguchi K, Machida N, Satoh T, Heydebreck A, Achiwa H, Doi T. A phase I dose expansion trial of avelumab (MSB0010718C), an anti-PD-L1 antibody, in Japanese patients with advanced gastric cancer. J Clin Oncol 2015; 33 Suppl15: 4047.
94. Morishita A, Gong J, Masaki T. Targeting receptor tyrosine kinases in gastric cancer. World J Gastroenterol 2014; 20: 4536-4545 [PMID: 24782606 DOI:10.3748/wjg.v20.i16.4536].
95. Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson AB. 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 2010; 28: 2947-2951 [PMID: 20458043 DOI:10.1200/JCO.2009.27.7988].
96. Martin-Richard M, Gallego R, Pericay C, Garcia Foncillas J, Queralt B, Casado E, Barriuso J, Iranzo V, Juez I, Visa L, Saigi E, Barnadas A, Garcia-Albeniz X, Maurel J. 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 2013; 31: 1573-1579 [PMID: 24077981 DOI:10.1007/s10637-013-0020-2].
97. Yamada Y, Kiyota N, Fuse N, Kato K, Minami H, Hashizume K, Kuroki Y, Ito Y, Ohtsu A. A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer. Gastric Cancer 2014; 17: 161-172 [PMID: 23532594 DOI:10.1007/s10120-013-0247-9].
98. Kim C, Lee JL, Choi YH, Kang BW, Ryu MH, Chang HM, Kim TW, Kang YK. Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. Invest New Drugs 2012; 30: 306-315 [PMID: 20839031 DOI:10.1007/s10637-010-9531-2].
99. Zheng J, de Guia T, Wang-Jairaj J, Newlands AH, Wang C, Crim C, Zhong N. Efficacy and safety of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg; 200/25 mcg) in Asian patients with chronic obstructive pulmonary disease: A randomized placebo-controlled trial. Curr Med Res Opin 2015; 31: 1191-1200 [PMID: 25830381 DOI:10.1185/03007995.2015.1036016].
100. Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houé V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D. Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC-A Randomized Phase III Trial. J Clin Oncol 2016; 34: 443-451 [PMID: 26628478 DOI:10.1200/JCO.2015.62.6598].
101. Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the secondline treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN - A randomized, phase III study. J Clin Oncol 2014; 32: 2039-2049 [PMID: 24868024 DOI:10.1200/JCO.2013.53.6136].
102. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303-312 [PMID: 23177514 DOI:10.1016/S0140-6736(12)61900-X].
103. Pavlakis N, Sjoquist KM, Tsobanis E, Martin AJ, Kang YK, Bang YJ, O'Callaghan CJ, Tebbutt NC, Rha SY, Lee J, Cho JY, Lipton LR, Burnell MJ, Alcindor T, Strickland A, Kim JW, Yip S, Simes J, Zalcberg JR, Goldstein D. INTEGRATE: A randomized, phase II, double-blind, placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC): A study by the Australasian Gastrointestinal Trials Group (AGITG)-Final overall and subgroup results. J Clin Oncol 2015; 33 Suppl15: 4003.
104. Bukowski RM, Yasothan U, Kirkpatrick P. Pazopanib. Nat Rev Drug Discov 2010; 9: 17-18 [PMID: 20043026 DOI:10.1038/nrd3073].
105. Thuss-Patience PC, Al-Batran SE, Siveke JT, Homann N, Malfertheiner P, Glaeser D, Stein A, Tamm I, Daum S, Potenberg J, Florschütz A, Vogel A, Ridwelski K, Ritgen M, Geissler M, Schmalenberg H, Schlattmann P, Lorenz M, Breithaupt K, Pichlmeier U. Pazopanib and 5-FU/oxaliplatin as first-line treatment in advanced gastric cancer: PaFLO, a randomized phase II study from the AIO (Arbeitsgemeinschaft Internistische Onkologie). J Clin Oncol 2015; 33 Suppl15: 4033.
106. Lee MY, Kim ST, Lee J, Park SH, Park YS, Lim HY, Kang WK, Park JO. Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer. J Clin Oncol 2015; 33 Suppl15: 4049.
107. ClinicalTrials.gov. Phase II Study of Neoadjuvant XELOX Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis (accessed January 14, 2016). Available from: URL: http://www.clinicaltrials.gov/ct/show/NCT02015169.
108. ClinicalTrials.gov. FOLFOX Plus Regorafenib in Patients With Unresectable or Metastatic Esophagogastric Cancer (accessed January 14, 2016). Available from: URL: http://www.clinicaltrials.gov/ct/show/NCT01913639.