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1
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Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial. Gastric Cancer 2019; 22:817-827. [PMID: 30515672 PMCID: PMC6570778 DOI: 10.1007/s10120-018-0903-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in several advanced cancers. We report results from JAVELIN Solid Tumor JPN, a phase 1 trial of avelumab in Japanese patients with advanced solid tumors with expansion in patients with advanced gastric cancer/gastroesophageal junction cancer. METHODS In the dose-escalation part, eligible patients had various previously treated metastatic or advanced solid tumors. In the dose-expansion part, patients had stage IV gastric cancer/gastroesophageal junction adenocarcinoma and disease progression after prior therapy that included a platinum and fluoropyrimidine agent. Patients received avelumab every 2 weeks intravenously at 3, 10, or 20 mg/kg during dose escalation and 10 mg/kg during dose expansion. RESULTS Among 17 patients who received avelumab in the dose-escalation part, no dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. 40 patients were enrolled in the dose-expansion part, of whom 21 (52.5%) had received ≥ 3 prior lines of therapy for advanced disease. In these patients, the objective response rate was 10.0% (95% CI, 2.8-23.7%) and median overall survival was 9.1 months (95% CI, 7.2-11.2 months). Three of 40 patients (7.5%) had a grade 3 treatment-related adverse event (alanine aminotransferase increase, anemia, and hyponatremia), and no grade ≥ 4 treatment-related adverse events occurred. Five patients (12.5%) had an immune-related adverse event (all grade 1/2). CONCLUSIONS Avelumab showed acceptable safety in Japanese patients with advanced solid tumors and clinical activity in patients with advanced gastric cancer/gastroesophageal junction cancer and disease progression after chemotherapy.
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Coccolini F, Fugazzola P, Ansaloni L, Sartelli M, Cicuttin E, Leandro G, De' Angelis GL, Gaiani F, Di Mario F, Tomasoni M, Catena F. Advanced gastric cancer: the value of systemic and intraperitoneal chemotherapy. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:104-109. [PMID: 30561427 PMCID: PMC6502214 DOI: 10.23750/abm.v89i8-s.7904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Indexed: 12/20/2022]
Abstract
Several possibilities in treating advanced gastric cancer exist. Radical surgery associated with chemotherapy represents the cornerstone. Which one is more effective among neoadjuvant, adjuvant or perioperative chemotherapy is still a matter of debate. Several innovative results showed the necessity to keep increasingly into consideration the intraperitoneal administration of chemotherapies. Moreover, classical drugs and their ways of administration should be combined with the new ones to improve results. Lastly the prevention of recurrence should be considered: one possibility is to administer intraperitoneal chemotherapy earlier in the therapeutic algorithm.
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Affiliation(s)
- Federico Coccolini
- Emergency, General and Trauma Surgery dept., Bufalini hospital, Cesena, Italy.
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3
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Kojima T, Yamazaki K, Kato K, Muro K, Hara H, Chin K, Goddemeier T, Kuffel S, Watanabe M, Doi T. Phase I dose-escalation trial of Sym004, an anti-EGFR antibody mixture, in Japanese patients with advanced solid tumors. Cancer Sci 2018; 109:3253-3262. [PMID: 30099818 PMCID: PMC6172077 DOI: 10.1111/cas.13767] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 07/20/2018] [Accepted: 07/29/2018] [Indexed: 12/25/2022] Open
Abstract
Sym004 is a 1:1 mixture of two antibodies targeting non‐overlapping epitopes of the epidermal growth factor receptor that antagonizes ligand binding and induces receptor downregulation. In preclinical models, it has superior antitumor activity to cetuximab and panitumumab. Japanese adults aged ≥20 years with an Eastern Cooperative Oncology Group status of 0/1 and life expectancy ≥3 months were eligible. Patients in Part A (dose escalation) had refractory or recurrent late‐stage solid tumors and received Sym004 6 mg/kg/wk (n = 3), 9 mg/kg loading/6 mg/kg/wk (n = 6), 12 mg/kg/wk (n = 6), or 18 mg/kg biweekly (n = 6). Patients in expansion Part B (n = 30) had esophageal squamous cell carcinoma and received Sym004 at the dose recommended from Part A. Fifty‐one patients received Sym004. No dose‐limiting toxicities were observed in Part A. A dose of 12 mg/kg/wk was selected for Part B. All patients in Part B experienced treatment‐related adverse events, most commonly dermatitis acneiform (76.7%). Eighteen grade ≥3 treatment‐related adverse events and five serious adverse events occurred (cardiac arrest, lung infection, interstitial lung disease, toxic skin eruption, blood creatinine increase). Two patients had treatment‐related adverse events resulting in death (cardiac arrest and blood creatinine increase). Five patients in Part B had a best overall response of partial response, 12 stable diseases and 12 disease progression (1 not evaluable). The objective response rate was 16.7% (95% CI: 5.6%‐34.7%). Sym004 therapy was well tolerated with no dose‐limiting toxicities at any dose studied. Evidence of antitumor activity was seen in patients with esophageal squamous cell carcinoma. ClinicalTrials.gov Identifier: NCT01955473.
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Affiliation(s)
- Takashi Kojima
- National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | | | - Ken Kato
- National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kei Muro
- Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Japan
| | - Hiroki Hara
- Saitama Cancer Center, Kita Adachi-gun, Saitama, Japan
| | - Keisho Chin
- The Cancer Institute Hospital of JFCR, Ariake, Koto, Tokyo, Japan
| | | | | | | | - Toshihiko Doi
- National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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4
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Gaur P, Hunt CR, Pandita TK. Emerging therapeutic targets in esophageal adenocarcinoma. Oncotarget 2018; 7:48644-48655. [PMID: 27102294 PMCID: PMC5217045 DOI: 10.18632/oncotarget.8777] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 04/10/2016] [Indexed: 12/18/2022] Open
Abstract
The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.
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Affiliation(s)
- Puja Gaur
- Department of General Surgery, Division of Thoracic Surgery, The Houston Methodist Research Institute, Houston, TX, USA
| | - Clayton R Hunt
- Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX, USA
| | - Tej K Pandita
- Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX, USA
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5
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Li T, Liu X, Shen Q, Yang W, Huo Z, Liu Q, Jiao H, Chen J. Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis. Oncotarget 2018; 7:26580-92. [PMID: 27058891 PMCID: PMC5042000 DOI: 10.18632/oncotarget.8555] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 03/12/2016] [Indexed: 12/12/2022] Open
Abstract
Anti-angiogenesis targeting VEGFR2 has been an attractive strategy for cancer therapy for its role in promoting cancer growth and metastasis. However, the currently available drugs have unexpected side effects. Therefore, development of novel VEGFR2 inhibitors with less toxicity would be of great value. In this study, we describe a novel and safely VEGFR2 inhibitor, Salinomycin (Sal), which was screened from the drug libraries of Food and Drug Administration (FDA) and prohibited the binding of the ATP at its binding pocket of VEGFR2 using molecular docking model. Sal could interfere a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation in HUVECS in vitro. Matrigel plug model demonstrated Sal strongly inhibited angiogenesis in vivo. We found that Sal significantly decreased VEGF-induced phosphorylation of VEGFR2 and its downstream STAT3 in dose- and time-dependent manner in HUVECs. Besides, Sal could directly reduce the cell viability and induce apoptosis in SGC-7901 cancer cells in vitro. Sal inhibited constitutive STAT3 activation by blocking its DNA binding and reduced various gene products including Bcl-2, Bcl-xL and VEGF both at mRNA and protein levels. Intra-peritoneal injection of Sal at doses of 3 and 5 mg/kg/day markedly suppressed human gastric cancer xenografts angiogenesis and growth without causing obvious toxicities. Taken together, Sal inhibits tumor angiogenesis and growth of gastric cancer; our results reveal unique characteristics of Sal as a promising anticancer drug candidate.
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Affiliation(s)
- Tao Li
- Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoxia Liu
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
| | - Qin Shen
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
| | - Wenjun Yang
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
| | - Zhenghao Huo
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
| | - Qilun Liu
- Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China
| | - Haiyan Jiao
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
| | - Jing Chen
- Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.,Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
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Liu ZH, Zhang Q, Ding YJ, Ren YH, Yang HP, Xi Q, Cheng YN, Miao GL, Liu HK, Li CX, Yan WQ, Li Y, Xue Z, Zhang L, Li XY, Zhao CL, Da Y, Wu XZ, Chen JQ, Zhang R, Li ZG. Overexpression of CHD1L is associated with poor survival and aggressive tumor biology in esophageal carcinoma. Oncotarget 2017; 8:74178-74187. [PMID: 29088777 PMCID: PMC5650332 DOI: 10.18632/oncotarget.18830] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/04/2017] [Indexed: 12/26/2022] Open
Abstract
Esophageal carcinoma (EC) is a malignancy with high metastatic potential. Chromosomal helicase/ATPase DNA binding protein 1-like (CHD1L) gene is a newly identified oncogene located at Chr1q21, and it is amplified in many solid tumors. However, the status of CHD1L protein expression in EC and its clinical significance is uncertain. This study was designed to investigate the significance of CHD1L expression in human EC and its biological function in EC cells. The expression of CHD1L was examined by immunohistochemistry in 191 surgically resected ECs. The associations between CHD1L expression and clinical pathological parameters and the prognostic value of CHD1L were analyzed. Western blot analysis showed that CHD1L was overexpressed in EC cell lines. In addition, positive CHD1L expression was strongly related to advanced clinical stage (P<0.01), and lymph node metastasis (P<0.01) of EC. The Kaplan-Meier curve indicated that high expression of CHD1L may result in poor prognosis of EC patients (P<0.01), and multivariate analysis showed that CHD1L overexpression was an independent predictor of overall survival. Furthermore, suppression of CHD1L in EC cells increased apoptosis and decreased cell proliferation invasion ability. Our results suggest that CHD1L is a target oncogene with the potential to serve as a novel prognostic biomarker in EC pathogenesis.
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Affiliation(s)
- Ze-Han Liu
- Nankai Clinical College, Tianjin Medical University, Tianjin, P.R. China
| | - Qi Zhang
- Institute of Integrative Medicine Therapy for Acute Abdominal Diseases of Tianjin, Nankai Hospital, Tianjin, P. R. China
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Yi-Jie Ding
- First Central Clinical College, Tianjin Medical University, Tianjin, P.R. China
| | - Ying-Hui Ren
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Hui-Peng Yang
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Qing Xi
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Ying-Nan Cheng
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Guo-Lin Miao
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Hong-Kun Liu
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Cai-Xia Li
- Institute of Integrative Medicine Therapy for Acute Abdominal Diseases of Tianjin, Nankai Hospital, Tianjin, P. R. China
| | - Wen-Qiang Yan
- Department of Thoracic Surgery, Nankai Hospital, Nankai District, Tianjin, P. R. China
| | - Yan Li
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Zhenyi Xue
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Lijuan Zhang
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Xin-Ye Li
- General Hospital, Tianjin Medical University, Tianjin, P.R. China
| | - Chen-Long Zhao
- General Hospital, Tianjin Medical University, Tianjin, P.R. China
| | - Yurong Da
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
| | - Xian-Zhong Wu
- Institute of Integrative Medicine Therapy for Acute Abdominal Diseases of Tianjin, Nankai Hospital, Tianjin, P. R. China
| | - Jun-Qiang Chen
- Department of Radiotherapy, Fujian Provincial Tumor Hospital, Affiliated Tumor Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Rongxin Zhang
- Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin, P.R. China
- Laboratory of Immunology and Inflammation, Guangdong Pharmaceutical University, Guangzhou, P.R. China
| | - Zhi-Gang Li
- Institute of Integrative Medicine Therapy for Acute Abdominal Diseases of Tianjin, Nankai Hospital, Tianjin, P. R. China
- General Hospital, Tianjin Medical University, Tianjin, P.R. China
- Hainan Cancer Hospital, Affiliated Cancer Hospital of Hainan Medical College, Haikou City, P.R. China
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7
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Karpińska-Kaczmarczyk K, Lewandowska M, Ławniczak M, Białek A, Urasińska E. Expression of Mismatch Repair Proteins in Early and Advanced Gastric Cancer in Poland. Med Sci Monit 2016; 22:2886-92. [PMID: 27527654 PMCID: PMC4996049 DOI: 10.12659/msm.897150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/05/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Mutations in DNA of mismatch repair (MMR) genes result in failure to repair errors that occur during DNA replication in microsatellites, resulting in accumulation of frameshift mutations in these genes and leading to DNA mismatch replication errors and microsatellite instability. Gastric cancers (GCs) with high MSI (MSI-H) are a well-defined subset of carcinomas showing distinctive clinicopathological features. In this study we investigated the rate of MSI and the correlation between MSI status and clinicopathological features of GC. MATERIAL AND METHODS The study included 107 patients with GCs: 61 with advanced gastric cancers (AGC) and 46 with early gastric cancer (EGC). MSI deficiency in GCs was assessed by the immunohistochemical analysis of expression of MMR proteins - MLH1, MSH2, MSH6, and PMS2 - using formalin-fixed and paraffin-embedded tissue. RESULTS A total of 6 (5.6%) MSI-H were observed. The loss of MMR proteins expression was associated with the intestinal type of GC in Lauren classification, and tubular and papillary architecture in WHO classification. There was no statistically significant association between negative MMR expression and other selected clinical parameters: age, sex, tumor location, depth of invasion (EGC and AGC), lymph nodes status, presence of the ulceration, and lymphocytic infiltrate. CONCLUSIONS In the present era of personalized medicine, the histological type of GC and MMR proteins status in cancer cells are very important for the proper surveillance of patients with familial GC and sporadic GCs, as well as for selecting the proper follow-up and treatment. Larger collaborative studies are needed to verify the features of MSI-H GCs in Poland.
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Affiliation(s)
| | | | | | - Andrzej Białek
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
| | - Elżbieta Urasińska
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
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8
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Lazăr DC, Tăban S, Cornianu M, Faur A, Goldiş A. New advances in targeted gastric cancer treatment. World J Gastroenterol 2016; 22:6776-6799. [PMID: 27570417 PMCID: PMC4974579 DOI: 10.3748/wjg.v22.i30.6776] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/13/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.
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9
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Ishida M, Kagawa S, Shimoyama K, Takehara K, Noma K, Tanabe S, Shirakawa Y, Tazawa H, Kobayashi H, Fujiwara T. Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer. Mol Cancer Ther 2016; 15:402-11. [PMID: 26832799 PMCID: PMC4783182 DOI: 10.1158/1535-7163.mct-15-0644] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 12/09/2015] [Indexed: 12/30/2022]
Abstract
Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. We hypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer.
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Affiliation(s)
- Michihiro Ishida
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| | - Kyoko Shimoyama
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kiyoto Takehara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiro Noma
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shunsuke Tanabe
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuhiro Shirakawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Hisataka Kobayashi
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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10
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Ahrens TD, Timme S, Hoeppner J, Ostendorp J, Hembach S, Follo M, Hopt UT, Werner M, Busch H, Boerries M, Lassmann S. Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine. Epigenetics 2016; 10:431-45. [PMID: 25923331 DOI: 10.1080/15592294.2015.1039216] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.
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Key Words
- 5mC, 5-methylcytidine
- AZA, Azacytidine
- DAC, Decitabine
- DNMT, DNA (cytosine-5)-methyltransferase
- EAC, esophageal adenocarcinoma
- ESCC, esophageal squamous cell carcinoma
- FAIM, Fas apoptotic inhibitory molecule
- GEJ, gastro-esophageal junction
- H3Ac, histone H3 acetylation
- H3K4me3, histone H3 trimethylation at lysine 4
- H3K9Ac, histone 3 lysine 9 acetylation
- HDAC, histone deacetylases
- HDACi, HDAC inhibitor
- Hes-2, Hairy and enhancer of split 2
- SAHA, suberoylanilide hydroxamic acid
- TSA, Trichostatin A
- azacytidine/gene pathway regulation
- epigenetics/HDAC inhibitor
- esophageal cancer
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Affiliation(s)
- Theresa D Ahrens
- a Dept. of Pathology; University Medical Center ; Freiburg , Germany
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11
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Coccolini F, Montori G, Ceresoli M, Cima S, Valli MC, Nita GE, Heyer A, Catena F, Ansaloni L. Advanced gastric cancer: What we know and what we still have to learn. World J Gastroenterol 2016; 22:1139-1159. [PMID: 26811653 PMCID: PMC4716026 DOI: 10.3748/wjg.v22.i3.1139] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/25/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a common neoplastic disease and, more precisely, is the third leading cause of cancer death in the world, with differences amongst geographic areas. The definition of advanced gastric cancer is still debated. Different stadiating systems lead to slightly different stadiation of the disease, thus leading to variations between the single countries in the treatment and outcomes. In the present review all the possibilities of treatment for advanced gastric cancer have been analyzed. Surgery, the cornerstone of treatment for advanced gastric cancer, is analyzed first, followed by an investigation of the different forms and drugs of chemotherapy and radiotherapy. New frontiers in treatment suggest the growing consideration for intraperitoneal administration of chemotherapeutics and combination of traditional drugs with new ones. Moreover, the necessity to prevent the relapse of the disease leads to the consideration of administering intraperitoneal chemotherapy earlier in the therapeutical algorithm.
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