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Gastric Cancer Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

Gastric Cancer Signaling Pathway

Fig.1 Gastric cancer signaling pathway. Targeted agents (listed in orange boxes) include those in clinical use (colored in green) and those in preclinical or early phase development (colored in red) for the treatment of advanced stage gastric cancer.

An Introduction to Gastric cancer

Gastric cancer (GC) is one of the world's most common cancers. According to Lauren's histological classification gastric cancer is divided into two distinct histological groups-the intestinal and diffuse types. A more recent classification is based on mucin expression and distinguishes 4 types of gastric cancer: the gastric or foveolar type (G-type), the intestinal type (I-type), the gastric and intestinal mixed type (GI-type) and the neither gastric nor intestinal phenotypes (N-type). In I-type gastric cancer, p53 mutations and allelic deletions of the adenomatous polyposis coli (APC) gene are observed more frequently than in G-type gastric carcinoma. In contrast, microsatellite instability (MSI) is found more often in G-type than in I-type gastric cancer. In 1994, the World Health Organization has classified the Gram-negative spiral-shaped bacterium Helicobacter pylori as a class 1 carcinogen. Since then, it has become clear that one of the most prominent risk factors for spontaneous gastric carcinogenesis is infection with H. pylori. In tumor development, loss of control of cell growth and proliferation, loss of susceptibility to apoptosis, neovascularization through the induction of angiogenesis are important features of all tumors. Here, we show the main signaling pathway of altered gene regulation and therapy in gastric cancer.

1 Main Signaling Pathways in Gastric Cancer Therapy

1.1 RTK signaling cascade

This pathway is characterized by the action of four RTKreceptors: c-Met, HER, EGFR, VEGFR. The MAPK/Erk signaling cascade is activated by the RTK receptor, the docking protein is Shc, which binds the receptor to a guanylate exchange factor. Then the signal is transduced to the small molecule Ras, which in turn activates the cascade core units, including Raf, MEK1/2, Erk. The activated Erk dimer can regulate the target protein in the cytoplasm, and can also be transported into the nucleus to phosphorylate various transcription factors that regulate gene expression in the nucleus. Activation of the PI3K/AKT/mTOR pathway can be triggered by the activation of RTKs, PI3K-activating mutations and amplifications, loss of PTEN function due to deletions or mutations, and overexpression or activating mutations of AKT1. AKT1 not only activates S6K, but also inhibits phosphorylation of p53, which affects apoptosis regulation BCL-2, promotes protein synthesis and thus cell proliferation.

1.2 Hippo signaling cascade

In mammals, the Hippo signaling pathway provides tumor-suppressor signaling involved in regulation of diverse cellular processes such as proliferation, apoptosis, survival, migration and differentiation. Once inactivated, the  downstream components in this pathway, such as YAP1, TAZ, will be activated, which lead to tumorigenesis at last. Core to the Hippo pathway is a kinase cascade, the upstream molecules of Hippo signaling pathway, such as Mst1, Mob and WW45, often form a conserved kinase cassette. These molecules can phosphorylate and activate LATS1/2, LATS1/2 in turn phosphorylate and inactivate the YAP/TAZ complex. When dephosphorylated, YAP/TAZ translocate into the nucleus and interact with TEAD family and other transcription factors such CDX2 to induce expression of genes that promote cell proliferation and inhibit apoptosis.

1.3 The Hh signaling cascade

The Hh ligand has been found to be deregulated during the progression in gastric cancer, Hh proteins initiate signaling through binding to the canonical receptor Patched (PTCH1), Hh binding to PTCH1 results in derepression of the proto-oncogene Smoothened (SMO) that results in SMO accumulation and phosphorylation. SMO mediates the large cytoplasmic complex dissociates from the microtubules, and the full-length Gli transcriptional activator is translocated to the nucleus, leading to transcriptional activation of Hh target genes such as cyclin E, cyclin D. And its target genes control the major hallmarks of cancer and cancer stem cells including proliferation, survival, metastasis, angiogenesis and selfrenewal.

1.4 Wnt signaling cascade

Specific Wnt ligands bind to their target ‘frizzled’ membrane receptor and interfere with the multi‐protein destruction complex, resulting in downstream activation of gene transcription by β‐catenin. Simplistically, the multi‐protein destruction complex involves Axin and APC serving as scaffolds binding both β‐catenin and GSK3, to facilitate phosphorylation of β‐catenin by GSK‐3β. Phosphorylated β‐catenin is degraded in proteasomes by the ubiquination machinery. β-catenin abnormal activation occurs in gastric cancers and associates with nuclear transcription factors leading to the eventual transcription and expression of target genes such as c‐myc, c‐jun, and cyclin D1 that regulates cell proliferation, survival, morphology, migration, selfrenewal in stem cells, and specification of cell fate during embryonic development.

2 Gastric cancer diagnosis

2.1 Molecular Markers for Gastric cancer

As the significance of each genetic and epigenetic abnormality differs in gastric, and colorectal cancers, the roles of individual abnormalities should be sufficiently understood before these abnormalities are used in diagnosis. Over the past many years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. These abnormalities, which include telomerase activation, genetic instability, and abnormalities in oncogenes, tumor suppressor genes, cell-cycle regulators, cell adhesion molecules, and DNA repair genes, could be effective markers in the molecular diagnosis of gastric cancer.

In gastric cancer, p53, APC, and CD44 have been used as markers for differential diagnosis, and TGFα, EGFR, c-Met, HER2, cyclin E, p27Kip1, and CDC25B for degree of malignancy. For the screening of genetic instability, hMLH1 expression is examined. With PCR-SSCP and PCR-RFLP, deletions or mutations of the APC gene and the p53 gene are examined. Mutations of the p53 gene are analyzed in exons 5 to 8, and LOH is analyzed using polymorphism at the BamH1 site of the 3-untranslated region of the gene. Genetic instability is monitored by microsatellite assay. Four loci of two CA repeats and two poly A tracts are examined, and if two or more loci with replication errors are detected, MSI-H is considered to be present. For MSI-H, the presence or absence of mutation of hMLH1 and hMSH2 is determined by PCR-SSCP methods.

2.2 Protein Markers for Gastric cancer

An early diagnosis coupled with good treatment strategy for gastric cancer can significantly improve the survival rates.Hence, serum biomarkers that identify patients with high risk for gastric adenocarcinoma would increase the effectiveness of endoscopy and improve the early diagnosis rate. In past decades, studies have revealed several serum biomarkers for gastric cancer which comprise carcinoembryonic antigen, cancer antigen (CA) 19-9, and CA 72-4, among others.

Traditionally, the detection of serum markers was done using the enzyme-linked immunosorbent assay (ELISA). However, the disadvantage of this method is that it requires larger volumes of sample and incurs high costs compared to the recent method of multiplex detection. The Luminex® xMAP® technology enables the large numbers of biological tests to be conducted and analyzed quickly, cost-effectively, and accurately as compared to the ELISA tests.

3 Targeted therapy for gastric cancer

By identifying the molecular characteristics of GC, a classification of GC subtypes has been proposed, intracellular pathways that contribute to carcinogenesis have been elucidated, and driver genes have been recognized as potential therapeutic targets. Alterations in specific genes that play important roles in diverse cellular functions, such as cell adhesion, signal transduction, cell differentiation, development, metastasis, DNA repair, and glycosylation changes, have been identified. In Table 1-10, selected clinical trials of novel therapeutic targets for the treatment of GC are presented.

3.1 Gastric cancer therapy for RTK pathway

Trastuzumab, TS-1 are designed to target and block HER2 by inhibiting dimerization, by inducing antibody dependent cellular cytotoxicity, and by increasing receptor endocytosis. Cetuximab is an IgG1 monoclonal antibody that inhibits ligand binding to the EGFR and stimulates cellmediated cytotoxicity. Panitumumab is a recombinant, fully human, IgG2-monoclonal antibody that is highly selective for EGFR. Anti-VEGFR monoclonal antibody Ramucirumab is directed against the VEGFR2 that mediated the majority of downstream effects of VEGF in angiogenesis by binding to VEGFR as a receptor antagonist blocking VEGF/VEGFR. Apatinib highly selectively binds to and strongly inhibits VEGFR2 and decreases the VEGF-mediated endothelial cell migration, proliferation, and tumor microvascular density. Onartuzumab, ABT-700, AMG 337 blocks the binding of HGF to its receptor and inhibits HGF/c-MET-mediated response. The PI3K/AKT/mTOR pathway is frequently activated in GC, two classes of PI3K inhibitors have been evaluated for the treatment of GC: BKM120, PX-886, XL147, which target all PI3K family members; BYL719, which specifically target the p110 catalytic subunit of PI3K. MK-2206, GDC0068 as AKT inhibitors been evaluated in clinical trials. Everolimus is an oral mTOR inhibitor and was established as standard therapy in several types of cancer.

Table 1 Clinical trials of HER2 mAB Trastuzumab

Nct id Status Lead sponsor Study first posted
NCT02805829 Not yet recruiting Xuzhou Medical University June 20, 2016
NCT02901301 Recruiting Yonsei University September 15, 2016
NCT02726399 Active, not recruiting Memorial Sloan Kettering Cancer Center April 1, 2016
NCT01396707 Active, not recruiting Asan Medical Center July 19, 2011
NCT01939275 Active, not recruiting City of Hope Medical Center September 11, 2013
NCT01191697 Active, not recruiting Dana-Farber Cancer Institute August 31, 2010
NCT03556345 Recruiting RemeGen June 14, 2018
NCT03588533 Recruiting Sung Yong Oh July 17, 2018
NCT02205047 Recruiting European Organisation for Research and Treatment of Cancer - EORTC July 31, 2014
NCT02725424 Recruiting Chinese Academy of Medical Sciences April 1, 2016
NCT03409848 Recruiting AIO-Studien-gGmbH January 24, 2018
NCT02158988 Recruiting Charite University, Berlin, Germany June 9, 2014
NCT02578368 Recruiting Krankenhaus Nordwest October 16, 2015
NCT01928290 Active, not recruiting Washington University School of Medicine August 23, 2013
NCT02678182 Recruiting Royal Marsden NHS Foundation Trust February 9, 2016
NCT02318901 Active, not recruiting Western Regional Medical Center December 17, 2014
NCT03253107 Recruiting Kyungpook National University August 17, 2017
NCT01148849 Active, not recruiting MacroGenics June 22, 2010
NCT03319459 Recruiting Fate Therapeutics October 24, 2017
NCT03329690 Recruiting Daiichi Sankyo Co., Ltd. November 6, 2017
NCT02581462 Recruiting IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest October 21, 2015
NCT02393248 Recruiting Incyte Corporation March 19, 2015

According to statistics, a total of 22 Bevacizumab projects targeting gastric cancer HER2 are currently in clinical stage, of which 14 are recruiting and 8 are not recruiting.

Table 2 Clinical trials of HER2 inhibitor TS-1

Nct id Status Lead sponsor Study first posted
NCT03382600 Recruiting Merck Sharp & Dohme Corp. December 26, 2017
NCT01100801 Recruiting National University Hospital, Singapore April 9, 2010
NCT01761461 Recruiting Samsung Medical Center January 4, 2013
NCT03137004 Not yet recruiting Fujian Cancer Hospital May 2, 2017
NCT01285557 Active, not recruiting Taiho Oncology, Inc. January 28, 2011
NCT01795027 Active, not recruiting Sun Yat-sen University February 20, 2013
NCT02191566 Recruiting Kangbuk Samsung Hospital July 16, 2014

Table 3 Clinical trials of EGFR mAB Cetuximab

Nct id Status Lead sponsor Study first posted
NCT00183898 Active, not recruiting University of Southern California September 16, 2005
NCT02318901 Active, not recruiting Western Regional Medical Center December 17, 2014
NCT03319459 Recruiting Fate Therapeutics October 24, 2017

Table 4 Clinical trials of EGFR mAB Panitumumab

Nct id Status Lead sponsor Study first posted
NCT01443065 Active, not recruiting UNICANCER September 29, 2011

Table 5 Clinical trials of VEGFR mAB Ramucirumab

Nct id Status Lead sponsor Study first posted
NCT02726399 Active, not recruiting Memorial Sloan Kettering Cancer Center April 1, 2016
NCT02999295 Recruiting National Cancer Center, Japan December 21, 2016
NCT02934464 Recruiting Fondazione IRCCS Istituto Nazionale dei Tumori, Milano October 17, 2016
NCT02970539 Recruiting Kinex Pharmaceuticals Inc November 22, 2016
NCT02661971 Recruiting IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest January 25, 2016
NCT03008278 Recruiting National Cancer Institute (NCI) January 2, 2017
NCT03281369 Recruiting Hoffmann-La Roche September 13, 2017

Table 6 Clinical trials of VEGFR inhibitor Apatinib

Nct id Status Lead sponsor Study first posted
NCT03104283 Recruiting Affiliated Hospital of Qinghai University April 7, 2017
NCT03007446 Recruiting Chinese PLA General Hospital January 2, 2017
NCT02711969 Active, not recruiting Bukwang Pharmaceutical March 17, 2016
NCT03154983 Recruiting Zhou Fuxiang May 16, 2017
NCT02529878 Recruiting The First Affiliated Hospital of Zhejiang Chinese Medical University August 20, 2015
NCT02668380 Recruiting Peking Union Medical College Hospital January 29, 2016
NCT03428425 Not yet recruiting Hebei Medical University February 9, 2018
NCT02485015 Active, not recruiting The First People's Hospital of Changzhou June 30, 2015
NCT03271073 Recruiting Beijing Friendship Hospital September 1, 2017
NCT03144843 Recruiting Sun Yat-sen University May 9, 2017
NCT03333967 Recruiting The First Affiliated Hospital of Anhui Medical University November 7, 2017
NCT03276156 Recruiting Zhejiang Cancer Hospital September 8, 2017
NCT03042611 Recruiting LSK BioPartners Inc. February 3, 2017
NCT02697838 Recruiting Fujian Cancer Hospital March 3, 2016
NCT03349827 Recruiting Wuhan University November 22, 2017
NCT03478943 Recruiting Henan Cancer Hospital March 27, 2018
NCT03219593 Recruiting First Affiliated Hospital Bengbu Medical College July 17, 2017
NCT03334591 Recruiting Anhui Provincial Hospital November 7, 2017
NCT03531931 Not yet recruiting The First Affiliated Hospital of Xiamen University May 22, 2018
NCT03192735 Recruiting Chang-Ming Huang, Prof. June 20, 2017

According to statistics, a total of 20 Apatinib projects targeting gastric cancer VEGFR are currently in clinical stage, of which 16 are recruiting and 4 are not recruiting.

Table 7 Clinical trials of c-Met inhibitor AMG 337

Nct id Status Lead sponsor Study first posted
NCT02805829 Not yet recruiting Xuzhou Medical University June 20, 2016
NCT02901301 Recruiting Yonsei University September 15, 2016
NCT02726399 Active, not recruiting Memorial Sloan Kettering Cancer Center April 1, 2016
NCT01396707 Active, not recruiting Asan Medical Center July 19, 2011
NCT01939275 Active, not recruiting City of Hope Medical Center September 11, 2013
NCT01191697 Active, not recruiting Dana-Farber Cancer Institute August 31, 2010
NCT03556345 Recruiting RemeGen June 14, 2018
NCT03588533 Recruiting Sung Yong Oh July 17, 2018
NCT02205047 Recruiting European Organisation for Research and Treatment of Cancer - EORTC July 31, 2014
NCT02725424 Recruiting Chinese Academy of Medical Sciences April 1, 2016
NCT03409848 Recruiting AIO-Studien-gGmbH January 24, 2018
NCT02158988 Recruiting Charite University, Berlin, Germany June 9, 2014
NCT02578368 Recruiting Krankenhaus Nordwest October 16, 2015
NCT01928290 Recruiting Washington University School of Medicine August 23, 2013
NCT02678182 Recruiting Royal Marsden NHS Foundation Trust February 9, 2016
NCT02318901 Active, not recruiting Western Regional Medical Center December 17, 2014
NCT03253107 Recruiting Kyungpook National University August 17, 2017
NCT01148849 Active, not recruiting MacroGenics June 22, 2010
NCT03319459 Recruiting Fate Therapeutics October 24, 2017
NCT03329690 Recruiting Daiichi Sankyo Co., Ltd. November 6, 2017
NCT02581462 Recruiting IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest October 21, 2015
NCT02393248 Recruiting zIncyte Corporation March 19, 2015

According to statistics, a total of 23 AMG 337 projects targeting gastric cancer c-Met are currently in clinical stage, of which 15 are recruiting and 7 are not recruiting.

Table 8 Clinical trials of AKT inhibitor GDC0068

Nct id Status Lead sponsor Study first posted
NCT01896531 Active, not recruiting Genentech, Inc. July 11, 2013

Table 9 Clinical trials of mTOR inhibitor Everolimus

Nct id Status Lead sponsor Study first posted
NCT01514110 Active, not recruiting Chinese University of Hong Kong  

3.2 Gastric cancer therapy for Hippo pathway

Verteporfin was identified as YAP1 inhibitors. When livers were treated with VP, overgrowth induced by YAP overexpression, or by inactivation of NF2, was inhibited, thereby demonstrating the therapeutic potential of disrupting YAP1/TAZ-TEAD interactions.

3.3 Gastric cancer therapy for Hh pathway

Sonidegib, Buparlisib, Vismodegib, inhibit Hedgehog signaling through binding to SMO. However, in a phase II clinical trial of patients with metastatic colorectal cancer, treatment with vismodegib exhibited no incremental benefit in combination with FOLFOX.

Table 10 Clinical trials of SMO inhibitor Vismodegib

Nct id Status Lead sponsor Study first posted
NCT03052478 Recruiting Samsung Medical Center February 14, 2017
NCT02465060 Recruiting National Cancer Institute (NCI) June 8, 2015

3.4 Gastric cancer therapy for Wnt pathway

Despite the fact that the Wnt signaling pathway is more difficult to target compared with the Notch and Hh pathways, receptor/ligand interactions, cytosolic signaling components, and nuclear signaling components of the Wnt signaling pathway have been inhibited(e.g., the β-catenin antagonist, ICG-001 and PRI-724).

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