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Agri-Food By-Products in Cancer: New Targets and Strategies. Cancers (Basel) 2022; 14:cancers14225517. [PMID: 36428610 PMCID: PMC9688227 DOI: 10.3390/cancers14225517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/27/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
The globalization and the changes in consumer lifestyles are forcing us to face a deep transformation in food demand and in the organization of the entire food production system. In this new era, the food-loss and food-waste security nexus is relevant in the global debate and avoiding unsustainable waste in agri-food systems as well as the supply chain is a big challenge. "Food waste" is useful for the recovery of its valuable components, thus it can assume the connotation of a "food by-product". Sustainable utilization of agri-food waste by-products provides a great opportunity. Increasing evidence shows that agri-food by-products are a source of different bioactive molecules that lower the inflammatory state and, hence, the aggressiveness of several proliferative diseases. This review aims to summarize the effects of agri-food by-products derivatives, already recognized as promising therapeutics in human diseases, including different cancer types, such as breast, prostate, and colorectal cancer. Here, we examine products modulating or interfering in the signaling mediated by the epidermal growth factor receptor.
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2
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Deng YM, Zhao C, Wu L, Qu Z, Wang XY. Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR. Cell Death Dis 2022; 8:273. [PMID: 35641479 PMCID: PMC9156763 DOI: 10.1038/s41420-022-01064-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 01/01/2023]
Abstract
Cannabinoid receptors, CB1 and CB2, have been implicated as emerging targets for cancer therapy. Herein, we investigated the potential regulation mechanism of CB1 and its implications in colorectal cancer. CB1 and EGFR expression were examined in colorectal cancer cell lines. The effects of CB1 agonist ACEA and its antagonist AM251 on the proliferation, migration and invasion of colorectal cancer cells and the expression of M1 and M2 macrophage markers were examined. EGFR overexpression was performed with plasmids containing EGFR gene. Tumor xenografts were constructed to explore the effects of CB1 activation on tumorigenesis. We showed that CB1 was downregulated while EGFR was upregulated in colorectal cancer cells. The activation of CB1 suppressed the proliferation, migration and invasion of colorectal cancer cells and the differentiation of M2 macrophages, while CB1 inhibition had opposite effects. Moreover, the alterations in tumorigenesis and M2 macrophage activation induced by CB1 activation were counteracted by EGFR overexpression. Besides, CB1 silencing promoted tumor cell proliferation and M2 polarization which was counteracted by EGFR knockdown. In vivo, CB1 activation also repressed tumorigenesis and M2 macrophage activation. The present study demonstrated that CB1 activation suppressed M2 macrophage through EGFR downregulation in colorectal cancers. These findings first unveiled the potential avenue of CB1 as a targeted therapy for colorectal cancer.
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Affiliation(s)
- You-Ming Deng
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China
| | - Cheng Zhao
- Department of Endocrinology, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518037, Guangdong Province, P. R. China
| | - Lei Wu
- Research Institute of General Surgery, Jinling Hospital, Nanjing University, Nanjing, 210093, Jiangsu Province, P. R. China
| | - Zhan Qu
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China.
| | - Xin-Yu Wang
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, P. R. China
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Azadi A, Golchini A, Delazar S, Abarghooi Kahaki F, Dehnavi SM, Payandeh Z, Eyvazi S. Recent Advances on Immune Targeted Therapy of Colorectal Cancer Using bi-Specific Antibodies and Therapeutic Vaccines. Biol Proced Online 2021; 23:13. [PMID: 34193050 PMCID: PMC8245152 DOI: 10.1186/s12575-021-00147-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/12/2021] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is a universal heterogeneous disease that is characterized by genetic and epigenetic alterations. Immunotherapy using monoclonal antibodies (mAb) and cancer vaccines are substitute strategies for CRC treatment. When cancer immunotherapy is combined with chemotherapy, surgery, and radiotherapy, the CRC treatment would become excessively efficient. One of the compelling immunotherapy approaches to increase the efficiency of CRC therapy is the deployment of therapeutic mAbs, nanobodies, bi-specific antibodies and cancer vaccines, which improve clinical outcomes in patients. Also, among the possible therapeutic approaches for CRC patients, gene vaccines in combination with antibodies are recently introduced as a new perspective. Here, we aimed to present the current progress in CRC immunotherapy, especially using Bi-specific antibodies and dendritic cells mRNA vaccines. For this aim, all data were extracted from Google Scholar, PubMed, Scopus, and Elsevier, using keywords cancer vaccines; CRC immunotherapy and CRC mRNA vaccines. About 97 articles were selected and investigated completely based on the latest developments and novelties on bi-specific antibodies, mRNA vaccines, nanobodies, and MGD007.
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Affiliation(s)
- Ali Azadi
- Department of Medicine, De La Salle Health Sciences Institute, Dasmariñas, Philippines
| | - Alireza Golchini
- Cancer surgery Department; Shiraz Medical School, Shiraz University of medical Sciences, Shiraz, Iran
| | - Sina Delazar
- Department of Radiology, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Abarghooi Kahaki
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Dehnavi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Payandeh
- Immunology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Eyvazi
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
- Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran
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4
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Hosseini SS, Khalili S, Baradaran B, Bidar N, Shahbazi MA, Mosafer J, Hashemzaei M, Mokhtarzadeh A, Hamblin MR. Bispecific monoclonal antibodies for targeted immunotherapy of solid tumors: Recent advances and clinical trials. Int J Biol Macromol 2020; 167:1030-1047. [PMID: 33197478 DOI: 10.1016/j.ijbiomac.2020.11.058] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
Abstract
Bispecific antibodie (BsAbs) combine two or more epitope-recognizing sequences into a single protein molecule. The first therapeutic applications of BsAbs were focused on cancer therapy. However, these antibodies have grown to cover a wider disease spectrum, including imaging, diagnosis, prophylaxis, and therapy of inflammatory and autoimmune diseases. BsAbs can be categorized into IgG-like formats and non-IgG-like formats. Different technologies have been used for the construction of BsAbs including "CrossMAb", "Quadroma", "knobs-into-holes" and molecular cloning. The mechanism of action for BsAbs includes the induction of CDC, ADCC, ADCP, apoptosis, and recruitment of cell surface receptors, as well as activation or inhibition of signaling pathways. The first clinical trials included mainly leukemia and lymphoma, but solid tumors are now being investigated. The BsAbs bind to a tumor-specific antigen using one epitope, while the second epitope binds to immune cell receptors such as CD3, CD16, CD64, and CD89, with the goal of stimulating the immune response against cancer cells. Currently, over 20 different commercial methods have been developed for the construction of BsAbs. Three BsAbs are currently clinically approved and marketed, and more than 85 clinical trials are in progress. In the present review, we discuss recent trends in the design, engineering, clinical applications, and clinical trials of BsAbs in solid tumors.
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Affiliation(s)
- Seyed Samad Hosseini
- Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Saeed Khalili
- Department of Biology Sciences, Faculty of Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negar Bidar
- Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Mohammad-Ali Shahbazi
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Jafar Mosafer
- Nanotechnology Research center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, School of Paramedical Science, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mahmoud Hashemzaei
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA; Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
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5
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Zhang M, Hu W, Hu K, Lin Y, Feng Z, Yun JP, Gao N, Zhang L. Association of KRAS mutation with tumor deposit status and overall survival of colorectal cancer. Cancer Causes Control 2020; 31:683-689. [PMID: 32394229 PMCID: PMC7319095 DOI: 10.1007/s10552-020-01313-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 05/04/2020] [Indexed: 01/08/2023]
Abstract
PURPOSE To examine associations of KRAS mutation with tumor deposit status and overall survival in colorectal cancer (CRC) patients. METHODS This retrospective cohort study included patients with incidental CRC diagnosed during 2010-2014 and recorded statuses of KRAS and tumor deposit in the National Cancer Database of the USA. Multivariable logistic regression and time-varying Cox regression analyses were used. RESULTS We included 45,761 CRC patients with KRAS status (24,027 [52.5%] men, 24,240 [53.0%] < 65 years old, 17,338 [37.9%] with KRAS mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, KRAS mutation (versus wild type) was associated with tumor deposit presence (odds ratio = 1.11, 95% CI 1.02-1.20). KRAS mutation was also linked to worse overall survival of CRC patients regardless of tumor deposit status (adjusted Hazard ratio [HR] = 1.20, 95% CI 1.07-1.33 for CRC with tumor deposits, and adjusted HR = 1.24, 95% CI 1.14-1.35 or CRC without) or tumor stage (adjusted HR = 1.32, 95% CI 1.14-1.54 for early-stage and adjusted HR = 1.18, 95% CI 1.10-1.27 for late-stage). Microsatellite instability was associated with better overall survival in CRC without tumor deposit (adjusted HR = 0.89, 95% CI 0.79-0.99), but not in CRC with tumor deposit (adjusted HR = 1.12, 95% CI 0.97-1.30). CONCLUSION KRAS mutation is independently associated with tumor deposit presence and a worse overall survival in CRC patients.
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Affiliation(s)
- Meifang Zhang
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Pathology, Princeton Medical Center, 1 Plainsboro Rd, Plainsboro, NJ, 08536, USA
| | - Wenwei Hu
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Kun Hu
- Department of Pathology, University at Buffalo, Buffalo, NY, USA
| | - Yong Lin
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Biostatistics, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Zhaohui Feng
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
| | - Lanjing Zhang
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
- Department of Pathology, Princeton Medical Center, 1 Plainsboro Rd, Plainsboro, NJ, 08536, USA.
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA.
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
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Abbaszadegan MR, Keyvani V, Moghbeli M. Genetic and molecular bases of esophageal Cancer among Iranians: an update. Diagn Pathol 2019; 14:97. [PMID: 31470870 PMCID: PMC6717340 DOI: 10.1186/s13000-019-0875-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Esophageal cancer is one of the leading causes of cancer related deaths among the Iranians. There is still a high ratio of mortality and low 5 years survival which are related to the late onset and diagnosis. Majority of patients refer for the treatment in advanced stages of tumor progression. MAIN BODY It is required to define an efficient local panel of diagnostic and prognostic markers for the Iranians. Indeed such efficient specific panel of markers will pave the way to decrease the mortality rate and increase the 5 years survival among the Iranian patients via the early diagnosis and targeted therapy. CONCLUSION in present review we have reported all of the molecular markers in different signaling pathways and cellular processes which have been assessed among the Iranian esophageal cancer patients until now.
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Affiliation(s)
| | - Vahideh Keyvani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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7
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Fiedler D, Heselmeyer-Haddad K, Hirsch D, Hernandez LS, Torres I, Wangsa D, Hu Y, Zapata L, Rueschoff J, Belle S, Ried T, Gaiser T. Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence. Int J Cancer 2018; 144:1561-1573. [PMID: 30229897 DOI: 10.1002/ijc.31869] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/11/2018] [Accepted: 08/13/2018] [Indexed: 12/19/2022]
Abstract
Colorectal adenomas are common precancerous lesions with the potential for malignant transformation to colorectal adenocarcinoma. Endoscopic polypectomy provides an opportunity for cancer prevention; however, recurrence rates are high. We collected formalin-fixed paraffin-embedded tissue of 15 primary adenomas with recurrence, 15 adenomas without recurrence, and 14 matched pair samples (primary adenoma and the corresponding recurrent adenoma). The samples were analysed by array-comparative genomic hybridisation (aCGH) and single-cell multiplex interphase fluorescence in situ hybridisation (miFISH) to understand clonal evolution, to examine the dynamics of copy number alterations (CNAs) and to identify molecular markers for recurrence prediction. The miFISH probe panel consisted of 14 colorectal carcinogenesis-relevant genes (COX2, PIK3CA, APC, CLIC1, EGFR, MYC, CCND1, CDX2, CDH1, TP53, HER2, SMAD7, SMAD4 and ZNF217), and a centromere probe (CEP10). The aCGH analysis confirmed the genetic landscape typical for colorectal tumorigenesis, that is, CNAs of chromosomes 7, 13q, 18 and 20q. Focal aberrations (≤10 Mbp) were mapped to chromosome bands 6p22.1-p21.33 (33.3%), 7q22.1 (31.4%) and 16q21 (29.4%). MiFISH detected gains of EGFR (23.6%), CDX2 (21.8%) and ZNF217 (18.2%). Most adenomas exhibited a major clone population which was accompanied by multiple smaller clone populations. Gains of CDX2 were exclusively seen in primary adenomas with recurrence (25%) compared to primary adenomas without recurrence (0%). Generation of phylogenetic trees for matched pair samples revealed four distinct patterns of clonal dynamics. In conclusion, adenoma development and recurrence are complex genetic processes driven by multiple CNAs whose evaluations by miFISH, with emphasis on CDX2, might serve as a predictor of recurrence.
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Affiliation(s)
- David Fiedler
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kerstin Heselmeyer-Haddad
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Daniela Hirsch
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Leanora S Hernandez
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Irianna Torres
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Darawalee Wangsa
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yue Hu
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Luis Zapata
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.,Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CGR), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | | | - Sebastian Belle
- Department of Internal Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Central Interdisciplinary Endoscopy Unit, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Ried
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Timo Gaiser
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer. Br J Cancer 2018; 119:1464-1470. [PMID: 30467411 PMCID: PMC6288144 DOI: 10.1038/s41416-018-0293-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023] Open
Abstract
Background Liquid biopsy offers a minimally invasive alternative to tissue-based evaluation of mutational status in cancer. The goal of the present study was to evaluate the aggregate performance of OncoBEAM RAS mutation analysis in plasma of colorectal cancer (CRC) patients at 10 hospital laboratories in Spain where this technology is routinely implemented. Methods Circulating cell-free DNA from plasma was examined for RAS mutations using the OncoBEAM platform at each hospital laboratory. Results were then compared to those obtained from DNA extracted from tumour tissue from the same patient. Results The overall percentage agreement between plasma-based and tissue-based RAS mutation testing of the 236 participants was 89% (210/236; kappa, 0.770 (95% CI: 0.689–0.852)). Re-analysis of tissue from all discordant cases by BEAMing revealed two false negative and five false positive tumour tissue RAS results, with a final concordance of 92%. Plasma false negative results were found more frequently in patients with exclusive lung metastatic disease. Conclusions In this first prospective real-world RAS mutation performance comparison study, a high overall agreement was observed between results obtained from plasma and tissue samples. Overall, these findings indicate that the plasma-based BEAMing assay is a viable solution for rapid delivery of RAS mutation status to determine mCRC patient eligibility for anti-EGFR therapy.
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9
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Wang JL, Fang CL, Tzeng YT, Hsu HL, Lin SE, Yu MC, Bai KJ, Wang LS, Liu HE. Prognostic value of localization of epidermal growth factor receptor in lung adenocarcinoma. J Biomed Sci 2018; 25:53. [PMID: 29950164 PMCID: PMC6022489 DOI: 10.1186/s12929-018-0451-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 05/22/2018] [Indexed: 11/10/2022] Open
Abstract
Background The nuclear translocation of epidermal growth factor receptor (EGFR) has been considered to play a role in carcinogenesis. However, the relevance of differentially located EGFR proteins in lung cancer remains unclear. Methods We examined 161 patients with primary lung adenocarcinoma to detect EGFR expression in lung cancer cells using immunohistochemistry and determined the correlations of EGFR expression with clinical characteristics, EGFR mutations, and survival time. Moreover, we graded complete membranous staining with strong intensity as high membranous EGFR (mEGFR) expression, and nuclear EGFR staining with strong intensity as high nuclear (nEGFR) expression. Results The prevalence of high mEGFR and nEGFR expression in lung adenocarcinoma was 42.86 and 39.13%, respectively. After multivariate analyses, high mEGFR expression was associated with a significantly reduced mortality risk in older patients, those with a history of smoking, and those without brain metastasis (hazard ratio[95% confidential interval], HR[95% CI] = 0.55[0.32~ 0.92]; 0.51[0.26~ 0.98] and 0.56[0.33~ 0.94], in overall survival, respectively). An association between high nEGFR expression and early recurrence was observed in patients with metastasis (HR[95% CI] =1.68[1.05~ 2.68], in progression-free survival). Notably, patients with low mEGFR and low nEGFR expression had the lowest survival rate in cases without brain metastasis (p = 0.018) and with a history of smoking (p = 0.062) and total EGFR (any high mEGFR or nEGFR) expression indicated a more favorable response to platinum-based chemotherapy regardless of EGFR mutations (HR[95% CI] =0.33[0.12–0.92]; adjusted HR[95% CI] = 0.36[0.13~ 1.02] with the use of tyrosine kinase inhibitor). Conclusions EGFR proteins at different cellular locations in lung adenocarcinoma might influence the biology of cancer cells and are an independent indicator of more favorable prognosis and treatment response. Electronic supplementary material The online version of this article (10.1186/s12929-018-0451-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jinn-Li Wang
- Division of Hematology Oncology, Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan.,Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, Collage of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan
| | - Chia-Lang Fang
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan.,Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan
| | - Yu-Tien Tzeng
- Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan
| | - Han-Lin Hsu
- Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan
| | - Sey-En Lin
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan.,Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan
| | - Ming-Chih Yu
- Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan
| | - Kuan-Jen Bai
- Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan
| | - Liang-Shun Wang
- Graduate Institute of Clinical Medicine, Collage of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan.,Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, No.291, Zhongzheng Rd., Zhonghe District, New Taipei City, 23561, Taiwan
| | - Hsingjin Eugene Liu
- Graduate Institute of Clinical Medicine, Collage of Medicine, Taipei Medical University, 250 Wuxing St. Taipei, 11031, Taipei, Taiwan. .,Division of Hematology Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No.111, Sec. 3, Xinglong Rd, Wenshan Dist, 11696, Taipei, Taiwan.
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10
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Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res 2018; 24:2276-2284. [DOI: 10.1158/1078-0432.ccr-17-0646] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 10/31/2017] [Accepted: 02/26/2018] [Indexed: 11/16/2022]
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11
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Sobani ZA, Sawant A, Jafri M, Correa AK, Sahin IH. Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer. World J Clin Oncol 2016; 7:340-351. [PMID: 27777877 PMCID: PMC5056326 DOI: 10.5306/wjco.v7.i5.340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 07/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.
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12
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Sakai K, Tsurutani J, Yamanaka T, Yoneshige A, Ito A, Togashi Y, De Velasco MA, Terashima M, Fujita Y, Tomida S, Tamura T, Nakagawa K, Nishio K. Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing. PLoS One 2015; 10:e0121891. [PMID: 25954997 PMCID: PMC4425536 DOI: 10.1371/journal.pone.0121891] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 02/04/2015] [Indexed: 02/05/2023] Open
Abstract
Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (α = 2 x 10-5). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.
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Affiliation(s)
- Kazuko Sakai
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Junji Tsurutani
- Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University, Yokohama, Kanagawa, Japan
| | - Azusa Yoneshige
- Department of Pathology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Akihiko Ito
- Department of Pathology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yosuke Togashi
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Marco A. De Velasco
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Masato Terashima
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yoshihiko Fujita
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Shuta Tomida
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Takao Tamura
- Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
- * E-mail:
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13
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Luo HY, Xu RH. Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer. World J Gastroenterol 2014; 20:3858-3874. [PMID: 24744578 PMCID: PMC3983442 DOI: 10.3748/wjg.v20.i14.3858] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/11/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide. The treatment of advanced CRC has improved significantly in recent years. With the emergence of two targeted antibodies, cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab (Avastin), a vascular endothelial growth factor monoclonal antibody, the treatment of metastatic CRC has entered the era of personalized therapy. Predictive and prognostic biomarkers have, and will continue to, facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC (mCRC). In this review, we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
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14
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Choi YS, Yoon S, Kim KL, Yoo J, Song P, Kim M, Shin YE, Yang WJ, Noh JE, Cho HS, Kim S, Chung J, Ryu SH. Computational design of binding proteins to EGFR domain II. PLoS One 2014; 9:e92513. [PMID: 24710267 PMCID: PMC3977815 DOI: 10.1371/journal.pone.0092513] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 02/24/2014] [Indexed: 12/03/2022] Open
Abstract
We developed a process to produce novel interactions between two previously unrelated proteins. This process selects protein scaffolds and designs protein interfaces that bind to a surface patch of interest on a target protein. Scaffolds with shapes complementary to the target surface patch were screened using an exhaustive computational search of the human proteome and optimized by directed evolution using phage display. This method was applied to successfully design scaffolds that bind to epidermal growth factor receptor (EGFR) domain II, the interface of EGFR dimerization, with high reactivity toward the target surface patch of EGFR domain II. One potential application of these tailor-made protein interactions is the development of therapeutic agents against specific protein targets.
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Affiliation(s)
- Yoon Sup Choi
- Cancer Research Institute, Seoul National University School of Medicine, Seoul, Republic of Korea
- School of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- KT Institute of Convergence Technology, Seocho-gu, Seoul, Korea
| | - Soomin Yoon
- Cancer Research Institute, Seoul National University School of Medicine, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, Seoul National University School of Medicine, Seoul, Republic of Korea
| | - Kyung-Lock Kim
- Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Jiho Yoo
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Parkyong Song
- Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Minsoo Kim
- Cancer Research Institute, Seoul National University School of Medicine, Seoul, Republic of Korea
- Scripps Korea Antibody Institute, Chuncheon, Republic of Korea
| | - Young-Eun Shin
- Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Won Jun Yang
- Cancer Research Institute, Seoul National University School of Medicine, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, Seoul National University School of Medicine, Seoul, Republic of Korea
| | - Jung-eun Noh
- Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Hyun-soo Cho
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Sanguk Kim
- School of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- Division of IT Convergence Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- * E-mail: (SK); (JC); (SHR)
| | - Junho Chung
- Cancer Research Institute, Seoul National University School of Medicine, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, Seoul National University School of Medicine, Seoul, Republic of Korea
- * E-mail: (SK); (JC); (SHR)
| | - Sung Ho Ryu
- School of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- * E-mail: (SK); (JC); (SHR)
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15
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Khong TL, Thairu N, Larsen H, Dawson PM, Kiriakidis S, Paleolog EM. Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer. BMC Cancer 2013; 13:518. [PMID: 24180698 PMCID: PMC4228238 DOI: 10.1186/1471-2407-13-518] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 10/23/2013] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is characterised by hypoxia, which activates gene transcription through hypoxia-inducible factors (HIF), as well as by expression of epidermal growth factor (EGF) and EGF receptors, targeting of which has been demonstrated to provide therapeutic benefit in CRC. Although EGF has been demonstrated to induce expression of angiogenic mediators, potential interactions in CRC between EGF-mediated signalling and the hypoxia/HIF pathway remain uncharacterised. METHODS PCR-based profiling was applied to identify angiogenic genes in Caco-2 CRC cells regulated by hypoxia, the hypoxia mimetic dimethyloxallylglycine (DMOG) and/or EGF. Western blotting was used to determine the role of HIF-1alpha, HIF-2alpha and MAPK cell signalling in mediating the angiogenic responses. RESULTS We identified a total of 9 angiogenic genes, including angiopoietin-like (ANGPTL) 4, ephrin (EFNA) 3, transforming growth factor (TGF) β1 and vascular endothelial growth factor (VEGF), to be upregulated in a HIF dependent manner in Caco-2 CRC cells in response to both hypoxia and the hypoxia mimetic dimethyloxallylglycine (DMOG). Stimulation with EGF resulted in EGFR tyrosine autophosphorylation, activation of p42/p44 MAP kinases and stabilisation of HIF-1α and HIF-2α proteins. However, expression of 84 angiogenic genes remained unchanged in response to EGF alone. Crucially, addition of DMOG in combination with EGF significantly increased expression of a further 11 genes (in addition to the 9 genes upregulated in response to either DMOG alone or hypoxia alone). These additional genes included chemokines (CCL-11/eotaxin-1 and interleukin-8), collagen type IV α3 chain, integrin β3 chain, TGFα and VEGF receptor KDR. CONCLUSION These findings suggest that although EGFR phosphorylation activates the MAP kinase signalling and promotes HIF stabilisation in CRC, this alone is not sufficient to induce angiogenic gene expression. In contrast, HIF activation downstream of hypoxia/DMOG drives expression of genes such as ANGPTL4, EFNA3, TGFβ1 and VEGF. Finally, HIF activation synergises with EGF-mediated signalling to additionally induce a unique sub-group of candidate angiogenic genes. Our data highlight the complex interrelationship between tumour hypoxia, EGF and angiogenesis in the pathogenesis of CRC.
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Affiliation(s)
| | | | | | | | | | - Ewa M Paleolog
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College, London, UK.
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16
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Ishiguro M, Kotake K, Nishimura G, Tomita N, Ichikawa W, Takahashi K, Watanabe T, Furuhata T, Kondo K, Mori M, Kakeji Y, Kanazawa A, Kobayashi M, Okajima M, Hyodo I, Miyakoda K, Sugihara K. Study protocol of the B-CAST study: a multicenter, prospective cohort study investigating the tumor biomarkers in adjuvant chemotherapy for stage III colon cancer. BMC Cancer 2013; 13:149. [PMID: 23530572 PMCID: PMC3618253 DOI: 10.1186/1471-2407-13-149] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 03/20/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy. Several oral fluorouracil (5-FU) derivatives with different properties are available in Japan, but which drug is the most appropriate for each patient has not been established. Although efficacy prediction of 5-FU derivatives using expression of 5-FU activation/metabolism enzymes in tumors has been studied, it has not been clinically applied. METHODS/DESIGN The B-CAST study is a multicenter, prospective cohort study aimed to identify the patients who benefit from adjuvant chemotherapy with each 5-FU regimen, through evaluating the relationship between tumor biomarker expression and treatment outcome. The frozen tumor specimens of patients with stage III colon cancer who receives postoperative adjuvant chemotherapy are examined. Protein expression of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) are evaluated using enzyme-linked immunosorbent assay (ELISA). mRNA expression of TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyl transferase (OPRT) are evaluated using reverse transcription polymerase chain reaction (RT-PCR). The patients' clinical data reviewed are as follow: demographic and pathological characteristics, regimen, drug doses and treatment duration of adjuvant therapy, types and severity of adverse events, disease free survival, relapse free survival and overall survival. Then, relationships among the protein/mRNA expression, clinicopathological characteristics and the treatment outcomes are analyzed for each 5-FU derivative. DISCUSSION A total of 2,128 patients from the 217 institutions were enrolled between April 2009 and March 2012. The B-CAST study demonstrated that large-scale, multicenter translational research using frozen samples was feasible when the sample shipment and Web-based data collection were well organized. The results of the study will identify the predictors of benefit from each 5-FU derivative, and will contribute to establish the "personalized therapy" in adjuvant chemotherapy for colon cancer. TRIAL REGISTRATION ClinicalTrials.gov: NCT00918827, UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002013.
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Affiliation(s)
- Megumi Ishiguro
- Department of Surgical Oncology, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
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17
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Moghbeli M, Abbaszadegan MR, Farshchian M, Montazer M, Raeisossadati R, Abdollahi A, Forghanifard MM. Association of PYGO2 and EGFR in esophageal squamous cell carcinoma. Med Oncol 2013; 30:516. [PMID: 23456637 DOI: 10.1007/s12032-013-0516-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2013] [Accepted: 02/17/2013] [Indexed: 01/14/2023]
Abstract
Wnt signaling is an important evolutionary conserved pathway that is not only involved in determination of cellular development, self-renewal, and fate, but also has significant roles in tumor development and progression. Deregulation of the Wnt/β-catenin signaling pathway and aberrant expression of its components is commonly observed in solid tumors. Such aberrant regulation of Wnt signaling is commonly related to either malfunction of its components or crosstalk with other cellular processes such as the epidermal growth factor receptor (EGFR) signaling cascade. Therefore, identification of the roles of major involved components may be useful to identify new therapeutic targets for cancer treatment. In this study, we assessed EGFR and PYGO2 mRNA expression in tumors and margin normal tissues from 55 esophageal squamous cell carcinoma (ESCC) patients using real-time qRT-PCR, and evaluated clinicopathology relative to the two genes' expression levels. Significant PYGO2 and EGFR overexpression was observed in 30.9 % (P = 0.017) and 38.2 % (P = 0.006) of tumors, respectively. PYGO2 and EGFR expression were significantly associated not only with each other (P < 0.001), but also with tumor staging and depth (P < 0.001). Furthermore, PYGO2 expression was significantly correlated with the tumor grade (P = 0.043) and size (P = 0.023). We identify PYGO2 as a new molecular marker of invasive tumors, introducing its probable oncogenic role in ESCC progression and aggressiveness. In line with other reports, we also illustrate the oncogenic function of EGFR in the development of ESCC through advance stages. We also observed a significant correlation between PYGO2 and EGFR in ESCC tumors, which reveals a mutual convergent influence of these factors in tumor progression and development. Considering aberrant expression, mutual positive feedback, and the significant clinical relevance of these genes in ESCC, we introduce them as appropriate therapeutic targets in adjuvant therapy of ESCC.
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Affiliation(s)
- Meysam Moghbeli
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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KRAS mutation analysis on low percentage of colon cancer cells: the importance of quality assurance. Virchows Arch 2012; 462:39-46. [PMID: 23242173 DOI: 10.1007/s00428-012-1356-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 10/30/2012] [Accepted: 11/30/2012] [Indexed: 01/12/2023]
Abstract
KRAS mutation testing is mandatory for patients with metastatic colorectal cancer who are eligible for treatment with an epidermal growth factor receptor targeting agent, since tumors with a mutation are not sensitive to the drug. Several methods for mutation testing are in use and the need for external quality assurance has been demonstrated. An often little addressed but important issue in external quality assurance schemes is a low percentage of tumor cells in the test samples, where the analytical sensitivity of most tests becomes critical. Using artificial samples based on a mixture of cell lines with known mutation status of the KRAS gene, we assessed the reliability of a series of commonly used methods (Sanger sequencing, high resolution melting, pyrosequencing, and amplification refractory mutation system-polymerase chain reaction) on samples with 0, 2.5, 5, 10, and 15 % mutated cells. Nine laboratories throughout Europe participated and submitted a total of ten data sets. The limit of detection of each method differed, ranging from >15-5 % tumor cells. All methods showed a decreasing correct mutation call rate proportionally with decreasing percentage of tumor cells. Our findings indicate that laboratories and clinicians need to be aware of the decrease in correct mutation call rate proportionally with decreasing percentage of tumor cells and that external quality assurance schemes need to address the issue of low tumor cell percentage in the test samples.
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19
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Vickers MM, Karapetis CS, Tu D, O'Callaghan CJ, Price TJ, Tebbutt NC, Van Hazel G, Shapiro JD, Pavlakis N, Gibbs P, Blondal J, Lee U, Meharchand JM, Burkes RL, Rubin SH, Simes J, Zalcberg JR, Moore MJ, Zhu L, Jonker DJ. Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17. Ann Oncol 2012; 24:953-60. [PMID: 23144444 DOI: 10.1093/annonc/mds577] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.
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Affiliation(s)
- M M Vickers
- Department of Oncology, Tom Baker Cancer Centre, Calgary, Canada
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20
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Shashidharamurthy R, Bozeman EN, Patel J, Kaur R, Meganathan J, Selvaraj P. Immunotherapeutic strategies for cancer treatment: a novel protein transfer approach for cancer vaccine development. Med Res Rev 2012; 32:1197-1219. [PMID: 23059764 DOI: 10.1002/med.20237] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Cancer cells have developed numerous ways to escape immune surveillance and gain unlimited proliferative capacity. Currently, several chemotherapeutic agents and radiotherapy, either alone or in combination, are being used to treat malignancies. However, both of these therapies are associated with several limitations and detrimental side effects. Therefore, recent scientific investigations suggest that immunotherapy is among the most promising new approaches in modern cancer therapy. The focus of cancer immunotherapy is to boost both acquired and innate immunity against malignancies by specifically targeting tumor cells, and leaving healthy cells and tissues unharmed. Cellular, cytokine, gene, and monoclonal antibody therapies have progressively become promising immunotherapeutic approaches that are being tested for several cancers in preclinical models as well as in the clinic. In this review, we discuss recent advances in these immunotherapeutic approaches, focusing on new strategies that allow the expression of specific immunostimulatory molecules on the surface of tumor cells to induce robust antitumor immunity.
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Affiliation(s)
- Rangaiah Shashidharamurthy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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21
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Azizi E, Kittai A, Kozuch P. Antiepidermal growth factor receptor monoclonal antibodies: applications in colorectal cancer. CHEMOTHERAPY RESEARCH AND PRACTICE 2012; 2012:198197. [PMID: 23091721 PMCID: PMC3472558 DOI: 10.1155/2012/198197] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 06/12/2012] [Indexed: 01/19/2023]
Abstract
Patients with metastatic colorectal cancer have a poor prognosis and present a challenge to clinicians. The role of the antiepidermal growth factor receptor (EGFR) pathway in tumorogenesis and tumor progression has been well defined. This paper will review the use of anti-EGFR monoclonal antibodies in the treatment of operable, as well as metastatic colorectal cancer both in the setting of KRAS mutation unselected patients and later in KRAS wild-type patients. Active investigations designed to further identify predictive biomarkers that may be potentially druggable are reviewed as well.
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Affiliation(s)
- Efat Azizi
- Beth Israel Medical Center, Phillips Ambulatory Care Center, Continuum Cancer Centers of New York, 10 Union Square East, Suite 4C, New York, NY, USA ; Section of Hematology/Oncology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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22
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Fuentes D, Chacón L, Casacó A, Ledón N, Fernández N, Iglesias A, Hernández DR, Sánchez B, Pérez R. Effects of an epidermal growth factor receptor-based cancer vaccine on wound healing and inflammation processes in murine experimental models. Int Wound J 2012; 11:98-103. [PMID: 22947303 DOI: 10.1111/j.1742-481x.2012.01074.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Anti-epidermal growth factor receptor (EGFR) therapies have been proven clinically effective for a variety of epithelial tumours. Vaccination of mice with the extracellular domain (ECD) of autologous EGFR overcomes the tolerance to self-EGFR and has antimetastatic effect on EGFR+ tumour. Because EGF/EGFR-signalling plays an important role in the inflammation stage of wound healing, the main objective of this study was to explore the possible role of murine (m) EGFR-ECD vaccine in the croton-oil-induced ear oedema and wound healing process in mice as autologous experimental models, mimicking the possible post-surgical wound complication in patients treated with human EGFR-ECD/VSSP vaccine. Mice were intramuscularly immunised four times; biweekly with the mEGFR-ECD/VSSP/Mont. Seven days later, an 8 mm diameter, full-thickness skin wound was created on the back of each animal. Immunisation induced a strong specific humoral response against the mEGFR-ECD protein and a DTH dose-response curve but interestingly, animals treated with mEGFR-ECD/VSSP/Mont had similar inflammatory and healing speed responses compared to control ones. These data suggest that application of mEGFR-ECD/VSSP vaccine as a therapeutic approach in cancer patients could not elicit a poor healing process after surgery.
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Affiliation(s)
- Dasha Fuentes
- Biomodels Unit, National Center for Laboratory Animal Breeding, Finca Tirabeque, Boyeros, Havana, CubaCenter of Molecular Immunology, Atabey, Playa, Havana, Cuba
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23
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Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry. J Virol 2012; 86:10935-49. [PMID: 22855500 DOI: 10.1128/jvi.00750-12] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), the molecular mechanisms by which EGFR facilitates HCV entry are not well understood. Using the infectious cell culture HCV model (HCVcc), we demonstrate that the binding of HCVcc particles to human hepatocyte cells induces EGFR activation that is dependent on interactions between HCV and CD81 but not claudin 1. EGFR activation can also be induced by antibody mediated cross-linking of CD81. In addition, EGFR ligands that enhance the kinetics of HCV entry induce EGFR internalization and colocalization with CD81. While EGFR kinase inhibitors inhibit HCV infection primarily by preventing EGFR endocytosis, antibodies that block EGFR ligand binding or inhibitors of EGFR downstream signaling have no effect on HCV entry. These data demonstrate that EGFR internalization is critical for HCV entry and identify a hitherto-unknown association between CD81 and EGFR.
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24
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Davies DM, Foster J, van der Stegen SJC, Parente-Pereira AC, Chiapero-Stanke L, Delinassios GJ, Burbridge SE, Kao V, Liu Z, Bosshard-Carter L, van Schalkwyk MCI, Box C, Eccles SA, Mather SJ, Wilkie S, Maher J. Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Mol Med 2012; 18:565-76. [PMID: 22354215 PMCID: PMC3388141 DOI: 10.2119/molmed.2011.00493] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 02/16/2012] [Indexed: 11/06/2022] Open
Abstract
Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.
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Affiliation(s)
- David M Davies
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Julie Foster
- Centre for Molecular Oncology and Imaging, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Sjoukje J C van der Stegen
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Ana C Parente-Pereira
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Laura Chiapero-Stanke
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - George J Delinassios
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Sophie E Burbridge
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Vincent Kao
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Zhe Liu
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Leticia Bosshard-Carter
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - May C I van Schalkwyk
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - Carol Box
- Tumour Biology and Metastasis, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, Surrey, UK
| | - Suzanne A Eccles
- Tumour Biology and Metastasis, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, Surrey, UK
| | - Stephen J Mather
- Centre for Molecular Oncology and Imaging, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Scott Wilkie
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
| | - John Maher
- King’s College London, King’s Health Partners Integrated Cancer Center, Department of Research Oncology, Guy’s Hospital Campus, London, UK
- Department of Immunology, Barnet and Chase Farm National Health Service (NHS) Trust, Barnet, Hertfordshire, UK
- Department of Clinical Immunology and Allergy, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
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Yang X, Xiong H, Guan ZZ, Okai I, Ye D, Song Y, Li X, Wang L, Liu L, Du S, Lin D, Shao S. Higher expression of Caveolin-1 inhibits human small cell lung cancer (SCLC) apoptosis in vitro. Cancer Invest 2012; 30:453-62. [PMID: 22545709 DOI: 10.3109/07357907.2012.675384] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer, and its treatment is closely associated with apoptosis. Caveolin-1 plays an important role in the development of a variety of human cancers. This study sought to investigate the influence of Caveolin-1 on the apoptosis of SCLC in vitro. We demonstrate that higher expression of Caveolin-1 leads to inhibition of cisplatin and Ultraviolet Radiation (UVR)-induced apoptosis in SCLC cells; and also could decrease caspase-3 activity and increase the stability of Bcl-2 at the protein level. Our findings illuminate a potential molecular mechanism regarding CAV-1's role as anti-apoptosis protein.
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Affiliation(s)
- Xiaohan Yang
- Department of Histology and Embryology, Dalian Medical University, Dalian, China
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Karmakar P, Chakrabarti MK. Thermostable direct hemolysin diminishes tyrosine phosphorylation of epidermal growth factor receptor through protein kinase C dependent mechanism. Biochim Biophys Acta Gen Subj 2012; 1820:1073-80. [PMID: 22543197 DOI: 10.1016/j.bbagen.2012.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 04/09/2012] [Accepted: 04/11/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND Adequate evidence mounts to the fact that several bacteria and their toxins have protective or curative roles in colorectal cancers. Thermostable direct hemolysin (TDH), produced by Vibrio parahaemolyticus, down regulates cell proliferation in colon carcinoma cell lines. TDH induces Ca2+ influx from an extracellular environment accompanied by protein kinase C phosphorylation. Activated protein kinase C inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), the rational target of anti-colorectal cancer therapy. METHODS Immunoblotting analyses were performed to ascertain protein kinase C activation, EGFR status, EGFR phosphorylation and mitogen activated protein kinase (MAPK) activity. Flow cytometry analysis and ELISA reconfirmed tyrosine phosphorylation of EGFR and ERK activations, respectively. PKC-α siRNA knockdown was done to corroborate the involvement of PKC-α in the undertaken study. RESULTS Our study showed the translocation of PKC-α from cytosol to the membrane fraction in colon carcinoma cell lines on incubation with TDH. The EGFR tyrosine kinase activity exhibited a down regulation on TDH treatment which involved PKC-α, as confirmed by siRNA knockdown. Also ERK phosphorylation occurred on PKC-α activation. CONCLUSION TDH activated PKC-α down regulates EGFR tyrosine kinase activity by MEK dependent mechanism involving MAPK. GENERAL SIGNIFICANCE In this study we have seen that TDH has an implication in EGFR based therapeutic approach in colorectal cancer via PKC mediated mechanism.
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Affiliation(s)
- Poulomee Karmakar
- National Institute of Cholera and Enteric Diseases, Scheme-XM, Beliaghata, Kolkata, India
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Clinical significance of KRAS gene mutation and epidermal growth factor receptor expression in Japanese patients with squamous cell carcinoma of the larynx, oropharynx and hypopharynx. Int J Clin Oncol 2012; 18:454-63. [DOI: 10.1007/s10147-012-0402-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 03/01/2012] [Indexed: 10/28/2022]
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Hoda D, Simon GR, Garrett CR. Targeting colorectal cancer with anti-epidermal growth factor receptor antibodies: focus on panitumumab. Ther Clin Risk Manag 2011; 4:1221-7. [PMID: 19337429 PMCID: PMC2643103 DOI: 10.2147/tcrm.s4314] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Panitumumab is a fully humanized monoclonal antibody with a high degree of affinity for the extracellular domain of the epidermal growth factor receptor. Phase II clinical evaluation of this drug, when administered as a single agent, in patients with metastatic colorectal cancer refractory to chemotherapy, demonstrated a modest objective radiographic response rate with acceptable toxicity; the most frequently observed side effect is rash. A randomized phase III study in subjects with chemotherapy-refractory metastatic colorectal cancer documented a progression-free survival advantage in subjects treated with panitumumab plus best supportive care versus best supportive care alone; a difference in survival was not observed, likely due to the high cross over rate. Primary tumor KRAS mutation analysis performed in this study indicated that the benefit was confined to those patients whose tumors did not contain a KRAS mutation. Further studies with panitumumab will be required to develop biomarkers of response and to determine if panitumumab has a role in combination with cytotoxic chemotherapy. This article summarizes the current state-of-the-science knowledge on panitumumab therapy in the treatment of advanced colorectal cancer.
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Affiliation(s)
- Daanish Hoda
- Division of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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The Crosstalk of PTGS2 and EGF Signaling Pathways in Colorectal Cancer. Cancers (Basel) 2011; 3:3894-908. [PMID: 24213116 PMCID: PMC3763401 DOI: 10.3390/cancers3043894] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Revised: 10/07/2011] [Accepted: 10/09/2011] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) is now the second-leading cause of cancer deaths in the USA. Colorectal cancer progression and metastasis depends on the orchestration of the aberrant signaling pathways that control tumor cell proliferation, survival and migration/invasion. Epidemiological, clinical, and animal studies have demonstrated that prostaglandin-endoperoxide synthase 2 (PTGS2) and epithelial growth factor (EGF) signaling pathways play key roles in promoting colorectal cancer growth and metastasis. In this review, we highlight major advances in our understanding of the roles of PTGS2 and EGF signaling in colorectal cancer.
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Viral delivery for gene therapy against cell movement in cancer. Adv Drug Deliv Rev 2011; 63:671-7. [PMID: 21616108 DOI: 10.1016/j.addr.2011.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 04/15/2011] [Accepted: 05/07/2011] [Indexed: 12/17/2022]
Abstract
Viral delivery for cancer gene therapy is a promising approach, where traditional radiotherapy or chemotherapy to limit proliferation and movement of cancer cells has met resistance. Based on the new understanding of the biology of the viral vectors, therapeutic viral vectors for cancer gene therapy have been improved for greater safety and efficacy as well as transitioned from being non-replicating to replication-competent. Traditional oncolytic vectors have focused on eliminating tumor growth, while novel vectors simultaneously target epithelial-to-mesenchymal transition (EMT) in cancer cells, which could further prevent and reverse the aggressive tumor progression. In this review, we highlight the illustrative examples of cancer gene therapy in clinical trials as well as preclinical data and include proposals on methods to further enhance the safety and efficacy of oncolytic viral vectors in cancer gene therapy.
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Abstract
INTRODUCTION Cetuximab is a chimeric mAb with avidity for the EGFR higher than that of the natural ligands of the receptor. Preclinical studies showed that cetuximab demonstrated synergy with topoisomerase I inhibitors in the treatment of human colorectal cancer (CRC) cell lines in vivo. Subsequent clinical trials have shown that cetuximab can reverse resistance to topoisomerase I inhibitors in addition to having modest monotherapy activity. These studies led to accelerated provisional FDA approval of the drug for the treatment of patients with irinotecan-refractory metastatic CRC. Its clinical utility has been improved with the discovery of negative predictive biomarkers; these have shown that there is a lack of cetuximab benefit for patients whose tumors generally harbor a KRAS mutation, thus sparing these patients the toxicity of the agent which would not be of treatment benefit. AREAS COVERED This review covers the last decade of clinical trials that have determined the toxicity and efficacy of cetuximab when given to patients with CRC, as well as some of the molecular subgroups tumors from patients with CRC who appear to not derive benefit from this mAb. EXPERT OPINION Cetuximab has modest single-agent efficacy in the treatment of patients with metastatic CRC whose tumors do not harbor a KRAS mutation. In combination with irinotecan, it is associated with an overall survival (OS) and progression-free survival (PFS) advantage in first-line therapy in patients with KRAS non mutant metastatic CRC; it can be combined with irinotecan to overcome resistance in patients with KRAS non mutant CRC who have previously progressed on prior irinotecan chemotherapy. Future studies of putative biomarkers are likely to give additional information to clearly define which patients with metastatic CRC receive therapeutic benefit from cetuximab and other monoclonal anti-EGFR therapies.
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Affiliation(s)
- Christopher R Garrett
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 4095, USA.
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Mancuso A, Sollami R, Recine F, Cerbone L, Macciomei MC, Leone A. Patient with colorectal cancer with heterogeneous KRAS molecular status responding to cetuximab-based chemotherapy. J Clin Oncol 2010; 28:e756-8. [PMID: 20855834 DOI: 10.1200/jco.2010.30.5011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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De Hertogh G, Geboes KP. Practical and molecular evaluation of colorectal cancer: new roles for the pathologist in the era of targeted therapy. Arch Pathol Lab Med 2010; 134:853-63. [PMID: 20524863 DOI: 10.5858/134.6.853] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Colorectal cancer is the third most common cancer and the fourth most common cause of cancer death worldwide. Patient cases are discussed in multidisciplinary meetings to decide on the best management on an individual basis. Until recently, the main task of the pathologist in such teams was to provide clinically useful reports comprising staging of colorectal cancer in surgical specimens. The advent of total mesorectal excision and the application of anti-epidermal growth factor receptor (EGFR)-targeted therapies for selected patients with metastasized colorectal cancer have changed the role of the pathologist. OBJECTIVES To present the traditional role of the pathologist in the multidisciplinary team treating patients with colorectal cancer, to address the technique of total mesorectal excision and its implications for the evaluation of surgical specimens, to offer background information on the various EGFR-targeted therapies, and to review the currently investigated tissue biomarkers assumed to be predictive for efficacy of such therapies, with a focus on the role of the pathologist in determining the status of such biomarkers in individual tumors. DATA SOURCES This article is based on selected articles pertaining to biopsy evaluation of colorectal carcinoma and reviews of EGFR-targeted therapies for this cancer. All references are accessible via the PubMed database (US National Library of Medicine and the National Institutes of Health). CONCLUSIONS Pathologists play an increasingly important role in the diagnosis and management of colorectal cancer because of the advent of new surgical techniques and of targeted therapies. It is expected that this role will increase further in the near future.
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Affiliation(s)
- Gert De Hertogh
- Department of Pathology, University Hospitals KULeuven, Leuven, Belgium.
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Patil DT, Fraser CR, Plesec TP. KRAS testing and its importance in colorectal cancer. Curr Oncol Rep 2010; 12:160-7. [PMID: 20425075 DOI: 10.1007/s11912-010-0099-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Cetuximab and panitumumab are monoclonal antibodies used in the treatment of metastatic colorectal cancer (mCRC) by selectively targeting the epidermal growth factor receptor (EGFR) axis. Studies have shown that mutations in codons 12/13 of exon 2 of the KRAS gene render these therapies ineffective. As a result, the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend KRAS mutation testing in mCRC. Appropriate testing depends on the coordinated efforts of the entire treatment team, including the pathologist, who selects the tumor sample and testing platform as well as interprets and reports results. In addition to describing rationale and methodologies for KRAS mutation testing, the authors also summarize their algorithmic approach and elaborate the potential role of newer molecular biomarkers to predict anti-EGFR resistance in wild-type KRAS tumors.
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Affiliation(s)
- Deepa T Patil
- Department of Anatomic Pathology, Cleveland Clinic, L25, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010; 15:699-731. [PMID: 20584808 PMCID: PMC3228001 DOI: 10.1634/theoncologist.2010-0025] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 05/01/2010] [Indexed: 02/06/2023] Open
Abstract
Rapidly growing insights into the molecular biology of colorectal cancer (CRC) and recent developments in gene sequencing and molecular diagnostics have led to high expectations for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on molecular biomarkers are contradictory in their findings and the current reality is that no molecular marker, other than the KRAS gene in the case of epidermal growth factor receptor (EGFR)- targeted therapy for metastatic disease, has made it into clinical practice. Many markers investigated suffer from technical shortcomings, resulting from lack of quantitative techniques to capture the impact of the molecular alteration. This understanding has recently led to the more comprehensive approaches of global gene expression profiling or genome-wide analysis to determine prognostic and predictive signatures in tumors. In this review, an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability, epidermal growth factor receptor, KRAS, BRAF, CpG island methylator phenotype, cytotoxic T lymphocytes, forkhead box P3-positive T cells, receptor for hyaluronic acid-mediated motility, phosphatase and tensin homolog, and T-cell originated protein kinase, in patients with CRC is provided.
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Affiliation(s)
- Vanessa Deschoolmeester
- Laboratory of Cancer Research and Clinical Oncology, Department of Medical Oncology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
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Wadlow RC, Ryan DP. The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 2010; 116:3537-48. [DOI: 10.1002/cncr.25155] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Cejas P, López-Gómez M, Aguayo C, Madero R, de Castro Carpeño J, Belda-Iniesta C, Barriuso J, Moreno García V, Larrauri J, López R, Casado E, Gonzalez-Barón M, Feliu J. KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS One 2009; 4:e8199. [PMID: 20020061 PMCID: PMC2792724 DOI: 10.1371/journal.pone.0008199] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Indexed: 12/20/2022] Open
Abstract
Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status. Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006). Conclusions/Significance Our results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.
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Affiliation(s)
- Paloma Cejas
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
| | - Miriam López-Gómez
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
- Department of Medical Oncology, Infanta Sofía Hospital, Madrid, Spain
| | - Cristina Aguayo
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
| | - Rosario Madero
- Biostatistics Unit, La Paz University Hospital, Madrid, Spain
| | | | | | - Jorge Barriuso
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
| | | | - Javier Larrauri
- Department of Pathology, La Paz University Hospital, Madrid, Spain
| | - Rocío López
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
| | - Enrique Casado
- Department of Medical Oncology, Infanta Sofía Hospital, Madrid, Spain
| | | | - Jaime Feliu
- Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
- * E-mail:
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Borghaei H, Smith MR, Campbell KS. Immunotherapy of cancer. Eur J Pharmacol 2009; 625:41-54. [PMID: 19837059 DOI: 10.1016/j.ejphar.2009.09.067] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 09/15/2009] [Accepted: 09/23/2009] [Indexed: 02/09/2023]
Abstract
Major advances have been made in the field of immunology in the past two decades. A better understanding of the molecular and cellular mechanisms controlling the immune system has opened the door to many innovative and promising new cancer therapies that manipulate the immune response. For instance, toll-like receptor agonists have been shown to boost immune responses toward tumors. Also, a wide array of cell-based immunotherapies utilizing T cells, NK cells, and dendritic cells have been established. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. Here, we examine some of these immunotherapeutic approaches currently in use or testing to treat cancer, and we examine available evidence with regards to mechanism and efficacy of these treatments.
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Affiliation(s)
- Hossein Borghaei
- Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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Whitehall V, Tran K, Umapathy A, Grieu F, Hewitt C, Evans TJ, Ismail T, Li WQ, Collins P, Ravetto P, Leggett B, Salto-Tellez M, Soong R, Fox S, Scott RJ, Dobrovic A, Iacopetta B. A multicenter blinded study to evaluate KRAS mutation testing methodologies in the clinical setting. J Mol Diagn 2009; 11:543-52. [PMID: 19815694 DOI: 10.2353/jmoldx.2009.090057] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Evidence that activating mutations of the KRAS oncogene abolish the response to anti-epidermal growth factor receptor therapy has revolutionized the treatment of advanced colorectal cancer. This has resulted in the urgent demand for KRAS mutation testing in the clinical setting to aid choice of therapy. The aim of this study was to evaluate six different KRAS mutation detection methodologies on two series of primary colorectal cancer samples. Two series of 80 frozen and 74 formalin-fixed paraffin-embedded tissue samples were sourced and DNA was extracted at a central site before distribution to seven different testing sites. KRAS mutations in codons 12 and 13 were assessed by using single strand conformation polymorphism analysis, pyrosequencing, high resolution melting analysis, dideoxy sequencing, or the commercially available TIB Molbiol (Berlin, Germany) or DxS Diagnostic Innovations (Manchester, UK) kits. In frozen tissue samples, concordance in KRAS status (defined as consensus in at least five assays) was observed in 66/80 (83%) cases. In paraffin tissue, concordance was 46/74 (63%) if all assays were considered or 71/74 (96%) using the five best performing assays. These results demonstrate that a variety of detection methodologies are suitable and provide comparable results for KRAS mutation analysis of clinical samples.
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Affiliation(s)
- Vicki Whitehall
- Queensland Institute of Medical Research, Bancroft Building, 300 Herston Road, Herston Queensland 4029, Australia.
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Lai CH, Tseng JT, Lee YC, Chen YJ, Lee JC, Lin BW, Huang TC, Liu YW, Leu TH, Liu YW, Chen YP, Chang WC, Hung LY. Translational up-regulation of Aurora-A in EGFR-overexpressed cancer. J Cell Mol Med 2009; 14:1520-31. [PMID: 19799648 PMCID: PMC3829018 DOI: 10.1111/j.1582-4934.2009.00919.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5′-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.
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Affiliation(s)
- Chien-Hsien Lai
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Spindler KLG, Nielsen JN, Ornskov D, Brandslund I, Jakobsen A. Epidermal growth factor (EGF) A61G polymorphism and EGF gene expression in normal colon tissue from patients with colorectal cancer. Acta Oncol 2009; 46:1113-7. [PMID: 17851837 DOI: 10.1080/02841860701338853] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION EGF/EGFR interactions are important mechanisms behind colorectal tumour development and growth. Recently a single nucleotide polymorphism in the EGF gene has been identified (EGF A61G). It may be a potential predictor for survival of patients receiving EGFR-inhibitor cetuximab treatment, but the clinical importance and the functional influence on EGF gene expression levels in colorectal cancer (CRC) patients have not yet been further assessed. The aim of the present study was to investigate the relationship between EGF A61G genotype and EGF gene expression levels in colorectal adenocarcinomas and normal colon tissue. MATERIAL AND METHODS Eighty-one CRC patients were included in the study. Tissue samples from normal colon, adenocacinomas and corresponding blood samples were analysed by real-time PCR for EGF gene expression and EGF A61G genotype, respectively. RESULTS Thirty-three percent were AA, 48% and 19% A/G and G/G respectively. We found a significantly lower median age in the A/A group compared to the G/G group, suggesting a later time of diagnosis in the G/G patients. There was a significant difference between the median EGF gene expression among the three genotypes in normal colon (p < 0.001) but not in adenocarcinomas. Furthermore, the median EGF gene expression was lower in CRC tissue than in normal colon samples, (0.13 (range 0.01-6.4) vs. 0.76, (range 0.013-5.55)). CONCLUSION We suggest that EGF A61G genotype has a functional influence on EGF gene expression in normal colon in CRC patients. The clinical implications warrant further investigations in prospective trials.
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Abstract
In the US, colorectal cancer is the third leading cause of cancer-related death. Approximately 20% of patients present with metastatic disease, and an additional 30% to 40% develop metastasis during the course of their disease. Patients with metastatic colon cancer have a 5-year survival rate of only 11%. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant treatment is usually used in patients advanced stage disease. In particular, epidermal growth factor receptor (EGFR) inhibitor therapies have emerged as effective treatments in a subset of patients with metastatic colorectal carcinoma. Two anti-EGFR biologics, cetuximab and panitumumab, have been approved by the Food and Drug Administrations for the treatment of refractory metastatic colorectal carcinoma. Mounting evidence has shown that these therapies are ineffective in tumors with mutations of codons 12 and 13 of exon 2 of the KRAS gene. Because of this compelling data, the National Comprehensive Cancer Network and the American Society of Clinical Oncology have recommended determination of KRAS mutation status in all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy. Anatomic pathologists play an integral role in coordinating the testing for KRAS mutations, as this assay is performed on tissue samples selected by the pathologist. Herein, the authors present an up-to-date review of the biologic, clinical, and laboratory aspects of KRAS mutation testing in colorectal cancer.
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Berlin J, Posey J, Tchekmedyian S, Hu E, Chan D, Malik I, Yang L, Amado RG, Hecht JR. Panitumumab with Irinotecan/Leucovorin/5-Fluorouracil for First-Line Treatment of Metastatic Colorectal Cancer. Clin Colorectal Cancer 2009. [DOI: 10.1016/s1533-0028(11)70550-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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van Krieken JHJM, Jung A, Kirchner T, Carneiro F, Seruca R, Bosman FT, Quirke P, Fléjou JF, Plato Hansen T, de Hertogh G, Jares P, Langner C, Hoefler G, Ligtenberg M, Tiniakos D, Tejpar S, Bevilacqua G, Ensari A. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 2008; 453:417-31. [PMID: 18802721 DOI: 10.1007/s00428-008-0665-y] [Citation(s) in RCA: 220] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Revised: 08/21/2008] [Accepted: 08/21/2008] [Indexed: 12/21/2022]
Abstract
Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.
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Affiliation(s)
- J H J M van Krieken
- Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, 6500, HB, The Netherlands.
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Ramírez BS, Alpízar YA, Fernández DRH, Hidalgo GG, Capote AR, Rodríguez RP, Fernández LE. Anti-EGFR activation, anti-proliferative and pro-apoptotic effects of polyclonal antibodies induced by EGFR-based cancer vaccine. Vaccine 2008; 26:4918-26. [DOI: 10.1016/j.vaccine.2008.07.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2008] [Revised: 07/03/2008] [Accepted: 07/10/2008] [Indexed: 11/30/2022]
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Santoro A, Comandone A, Rimassa L, Granetti C, Lorusso V, Oliva C, Ronzoni M, Siena S, Zuradelli M, Mari E, Pressiani T, Carnaghi C. A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer. Ann Oncol 2008; 19:1888-93. [PMID: 18667394 DOI: 10.1093/annonc/mdn401] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gefitinib inhibits the epidermal growth factor receptor tyrosine kinase and preclinical studies indicate that it may enhance CPT-11 cytotoxicity. This randomized phase II trial investigates the feasibility and efficacy of gefitinib and 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) in patients with metastatic colorectal cancer. PATIENTS AND METHODS Patients were randomized to FOLFIRI +/- gefitinib 250 mg daily p.o. Patients randomized to FOLFIRI + gefitinib without disease progression after 6 months continued to receive gefitinib alone until disease progression. RESULTS From October 2002 to September 2004, 100 patients were enrolled. Twenty-three patients (47.9%) in the FOLFIRI arm and 23 (45.1%) in the FOLFIRI + gefitinib arm experienced an objective response. The median progression-free survival and overall survival were 8.3 and 18.6 months in the FOLFIRI arm, and 8.3 and 17.1 months in the FOLFIRI + gefitinib arm, respectively. In the combination arm, grades 3-4 adverse events were experienced by 35 (67.3%) patients versus 25 patients (52.1%) in the FOLFIRI arm; 12 patients (23.1%) withdrew for an adverse event in the FOLFIRI + gefitinib arm and 5 (10.4%) in the FOLFIRI arm. CONCLUSIONS These data show that adding gefitinib to FOLFIRI does not improve the efficacy of FOLFIRI regimen. These disappointing results could be related to the high toxicity observed that led to significant dose reductions and delays.
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Affiliation(s)
- A Santoro
- Unità Operativa di Oncologia e Ematologia, Istituto Clinico Humanitas, Rozzano, Italy
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Abstract
Monoclonal antibodies have become increasingly used therapeutic agents for the treatment of solid cancer. Many are now being tested as components of adjuvant or first-line therapies to assess their efficacy in improving or prolonging survival. Selected unconjugated antibodies can exert clinically significant antitumor effects in many cancers. Antibody conjugates have been used to deliver toxic principles, such as radioactive particles, chemotherapeutic agents, and catalytic toxins, with increasing success in clinical trials.
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Affiliation(s)
- David M Heimann
- Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
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Von Hippel-Lindau tumor suppressor gene loss in renal cell carcinoma promotes oncogenic epidermal growth factor receptor signaling via Akt-1 and MEK-1. Eur Urol 2008; 54:845-53. [PMID: 18243508 DOI: 10.1016/j.eururo.2008.01.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Accepted: 01/04/2008] [Indexed: 11/22/2022]
Abstract
OBJECTIVES Clear-cell renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is frequently associated with loss of von Hippel-Lindau (VHL) gene function, resulting in the aberrant transcriptional activation of genes that contribute to tumor growth and metastasis, including transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor (EGFR) tyrosine kinase. To determine the functional impact of EGFR activation on RCC, we suppressed critical components of this pathway: EGFR, Akt-1, and MEK-1. METHODS Stable transfection of RCC cells with plasmids bearing shRNA directed against each of these genes was used to individually suppress their expression. Transfectants were characterized for growth and invasiveness in vitro and tumorigenesis in vivo. RESULTS RCC cell transfectants displayed significantly reduced growth rate and matrix invasion in vitro and RCC tumor xenograft growth rate in vivo. Analysis of tumor cells that emerged after extended periods in each model showed that significant EGFR suppression was sustained, whereas Akt-1 and MEK-1 knock-down cells had escaped shRNA suppression. CONCLUSIONS EGFR, Akt-1, and MEK-1 are individually critical for RCC cell invasiveness in vitro and tumorigenicity in vivo, and even partial suppression of each can have a significant impact on tumor progression. The emergence of transfectants that had escaped Akt-1 and MEK-1 suppression during tumorigenicity experiments suggests that these effectors may each be more critical than EGFR for RCC tumorigenesis, consistent with results from clinical trials of EGFR inhibitors for RCC, where durable clinical responses have not been seen.
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Asano R, Sone Y, Makabe K, Tsumoto K, Hayashi H, Katayose Y, Unno M, Kudo T, Kumagai I. Humanization of the bispecific epidermal growth factor receptor x CD3 diabody and its efficacy as a potential clinical reagent. Clin Cancer Res 2007; 12:4036-42. [PMID: 16818703 DOI: 10.1158/1078-0432.ccr-06-0059] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Bispecific antibodies (BsAb) have been exploited as both cancer immunodiagnostics and cancer therapeutics and show promise in clinical trials of cancer imaging and therapy. For development of BsAbs as clinical reagents, we have focused on construction of small recombinant BsAbs, called bispecific diabodies. Here, we constructed and characterized a humanized bispecific diabody. EXPERIMENTAL DESIGN We have reported significant antitumor activity of an anti-epidermal growth factor receptor (EGFR) x anti-CD3 bispecific diabody (Ex3) in in vitro cytotoxicity assays and in vivo. We humanized the Ex3 diabody (hEx3) by grafting the complementarity-determining region and compared its biological properties with those of Ex3. We also tested its physiologic stability and ability to alter survival in xenografted mice. RESULTS The final yield of hEx3 was 10 times that of Ex3, and refolded hEx3 and Ex3 showed identical binding profiles in EGFR-positive cell lines and EGFR-transfected Chinese hamster ovary cells. hEx3 showed dose-dependent cytotoxicity to EGFR-positive cell lines, which could be specifically inhibited by parental monoclonal antibody IgGs against EGFR or CD3 antigens. The heterodimeric structure was retained in PBS for 6 months, and growth inhibition was maintained after incubation under physiologic conditions. Coadministration of hEx3 with T-LAK cells and interleukin-2 prolonged the survival of nude mice with human colon carcinoma. CONCLUSIONS The humanized diabody hEx3 is an attractive molecule for cancer therapy and may provide important insights into the development of EGFR-based cancer-targeting reagents.
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MESH Headings
- Animals
- Antibodies, Bispecific/immunology
- Antibodies, Bispecific/pharmacology
- Antibodies, Bispecific/therapeutic use
- Antigen-Antibody Reactions
- Antineoplastic Agents/immunology
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- CD3 Complex/immunology
- CHO Cells
- Carcinoma/drug therapy
- Carcinoma/immunology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cloning, Molecular
- Colonic Neoplasms/drug therapy
- Colonic Neoplasms/immunology
- Cricetinae
- Cricetulus
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- ErbB Receptors/immunology
- Flow Cytometry
- Humans
- Mice
- Mice, Nude
- Protein Binding
- Transplantation, Heterologous
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ryutaro Asano
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Japan
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