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Montemagno C, Cassim S, De Leiris N, Durivault J, Faraggi M, Pagès G. Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine? Int J Mol Sci 2021; 22:6413. [PMID: 34203923 PMCID: PMC8232627 DOI: 10.3390/ijms22126413] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), accounting for 90-95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of β-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients.
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Affiliation(s)
- Christopher Montemagno
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.D.); (G.P.)
- Institute for Research on Cancer and Aging of Nice, Centre Antoine Lacassagne, CNRS UMR 7284 and IN-SERM U1081, Université Cote d’Azur, 06200 Nice, France
- LIA ROPSE, Laboratoire International Associé Université Côte d’Azur—Centre Scientifique de Monaco, 98000 Monaco, Monaco
| | - Shamir Cassim
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.D.); (G.P.)
- LIA ROPSE, Laboratoire International Associé Université Côte d’Azur—Centre Scientifique de Monaco, 98000 Monaco, Monaco
| | - Nicolas De Leiris
- Nuclear Medicine Department, Grenoble-Alpes University Hospital, 38000 Grenoble, France;
- Laboratoire Radiopharmaceutiques Biocliniques, Univ. Grenoble Alpes, INSERM, CHU Grenoble Alpes, 38000 Grenoble, France
| | - Jérôme Durivault
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.D.); (G.P.)
- LIA ROPSE, Laboratoire International Associé Université Côte d’Azur—Centre Scientifique de Monaco, 98000 Monaco, Monaco
| | - Marc Faraggi
- Centre Hospitalier Princesse Grace, Nuclear Medicine Department, 98000 Monaco, Monaco;
| | - Gilles Pagès
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.D.); (G.P.)
- Institute for Research on Cancer and Aging of Nice, Centre Antoine Lacassagne, CNRS UMR 7284 and IN-SERM U1081, Université Cote d’Azur, 06200 Nice, France
- LIA ROPSE, Laboratoire International Associé Université Côte d’Azur—Centre Scientifique de Monaco, 98000 Monaco, Monaco
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Mehdipour P, Javan F, Jouibari MF, Khaleghi M, Mehrazin M. Evolutionary model of brain tumor circulating cells: Cellular galaxy. World J Clin Oncol 2021; 12:13-30. [PMID: 33552936 PMCID: PMC7829626 DOI: 10.5306/wjco.v12.i1.13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/05/2020] [Accepted: 11/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although circulating tumor cells (CTCs) have been the focus of consideration for a decade, a categorized cell-based diagnostic strategy is unavailable. The personalized management and complementary/analytical-strategy of data require an alphabetic guide. Therefore, we aimed to determine the behavior of CTCs in tumor and blood in order to provide the hypothetical-based agenda in the brain neoplasms. Exploring the protein expression (PE) using a single cell-based method would clarify the heterogeneity and diversity in tumor and blood, which are key events in the evolution in brain tumors. In fact, heterogeneity, diversity, and evolution are required for cancer initiation and progression. AIM To explore CTCs in brain tumors and blood cells and to assay intensity of PE through personalized insight. METHODS The focal population included 14 patients with meningioma, and four patients with metastatic brain tumors (T). PE was assayed by immunofluorescence in tumors cells and CTCs in 18 patients with brain tumors. Ratio test was applied between the T cells and CTCs in tumor tissue and in vascular system. T/CTC ratio-based classification of PE in macrophage chemoattractant chemokine ligand 2 (CCL2), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), CD133, cyclin E, neurofilament marker, cytokeratin 19, and leukocyte common antigen (CD45) were investigated. RESULTS Total analyzed cells ranged between 10794-92283 for tumor cells and between 117-2870 for CTCs. Characteristics of histopathologic and status of an ataxia-telangiectasia mutated polymorphism (D1853N) in 18 patients affected with brain tumors were also provided. The course of evolution and metastatic event relied on the elevated protein expression in CTCs, which could be considered as a prognostic value. Diverse protein expression of the migrated cells into the blood stream and the tumor was indicative of the occurrence of evolution. Besides, the harmonic co-expression between CCL2/EGF and CCL2/VEGF could facilitate the tumor progression including the metastatic event. Expression of these proteins in the migrated vasculature and into the buccal tissue offered a non-invasive follow-up detection in neoplastic disorders. PE-exploration of neurofilament marker/CD133/VEGF of the CTCs in meningioma and cytokeratin 19/CD45/ cyclin E in the patients with metastatic brain tumor would clarify the tumor biology of the brain neoplastic disorders. CONCLUSION The alphabetical base of the evolutionary mechanisms relies on dual-, triple-, and multi-models with diverse intensity of expression. In fact, cross-talk between initiative and the complementary channels defines the evolutionary insight in cancer. A diverse-model of protein expression, including low, medium, and high intensity, is the key requirement for the completed model. The cluster of cells with diverse expression and remarkable co-expression between CCL2/EGF/VEGF and NM/CD133/VEGF in CTCs may be indicative of probable invasiveness of the tumor. Furthermore, the mode of cytokeratin-19+/CD45- can be traced in the metastatic patients.
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Affiliation(s)
- Parvin Mehdipour
- Department of Medical Genetics, Tehran University of Medical Sciences, School of Medicine, Tehran 1417613151, Tehran, Iran
| | - Firoozeh Javan
- Department of Medical Genetics, Tehran University of Medical Sciences, School of Medicine, Tehran 1417613151, Tehran, Iran
| | | | - Mehdi Khaleghi
- Shariati Hospital, Tehran University of Medical Sciences, Tehran 1417613151, Tehran, Iran
| | - Masoud Mehrazin
- Tehran University of Medical Science, Tehran 1417613151, Tehran, Iran
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Le BT, Raguraman P, Kosbar TR, Fletcher S, Wilton SD, Veedu RN. Antisense Oligonucleotides Targeting Angiogenic Factors as Potential Cancer Therapeutics. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 14:142-157. [PMID: 30594893 PMCID: PMC6307321 DOI: 10.1016/j.omtn.2018.11.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 02/07/2023]
Abstract
Cancer is one of the leading causes of death worldwide, and conventional cancer therapies such as surgery, chemotherapy, and radiotherapy do not address the underlying molecular pathologies, leading to inadequate treatment and tumor recurrence. Angiogenic factors, such as EGF, PDGF, bFGF, TGF-β, TGF-α, VEGF, endoglin, and angiopoietins, play important roles in regulating tumor development and metastasis, and they serve as potential targets for developing cancer therapeutics. Nucleic acid-based therapeutic strategies have received significant attention in the last two decades, and antisense oligonucleotide-mediated intervention is a prominent therapeutic approach for targeted manipulation of gene expression. Clinical benefits of antisense oligonucleotides have been recognized by the U.S. Food and Drug Administration, with full or conditional approval of Vitravene, Kynamro, Exondys51, and Spinraza. Herein we review the scope of antisense oligonucleotides that target angiogenic factors toward tackling solid cancers.
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Affiliation(s)
- Bao T Le
- Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Prithi Raguraman
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Tamer R Kosbar
- Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Susan Fletcher
- Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Steve D Wilton
- Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Rakesh N Veedu
- Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia.
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Albert S, Arndt C, Koristka S, Berndt N, Bergmann R, Feldmann A, Schmitz M, Pietzsch J, Steinbach J, Bachmann M. From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells in vitro and in vivo. Oncotarget 2018; 9:25597-25616. [PMID: 29876011 PMCID: PMC5986651 DOI: 10.18632/oncotarget.25390] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/28/2018] [Indexed: 02/06/2023] Open
Abstract
CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and "on-target, off-tumor" reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR+ epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments in vivo, the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.
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Affiliation(s)
- Susann Albert
- UniversityCancerCenter (UCC) Dresden, Tumor Immunology, ‘Carl Gustav Carus’ Technische Universität Dresden, Dresden, Germany
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Stefanie Koristka
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Nicole Berndt
- German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ralf Bergmann
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Anja Feldmann
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Marc Schmitz
- German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Immunology, Medical Faculty, ‘Carl Gustav Carus’ Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany
| | - Jörg Steinbach
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
- National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany
| | - Michael Bachmann
- UniversityCancerCenter (UCC) Dresden, Tumor Immunology, ‘Carl Gustav Carus’ Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
- German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany
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Co-expression and prognostic significance of the HER family members, EGFRvIII, c-MET, CD44 in patients with ovarian cancer. Oncotarget 2018; 9:19662-19674. [PMID: 29731973 PMCID: PMC5929416 DOI: 10.18632/oncotarget.24791] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 03/02/2018] [Indexed: 12/23/2022] Open
Abstract
EGFR and HER-2 are important targets but none of the monoclonal antibodies or small molecule tyrosine kinase inhibitors specific for the HER members has been approved for the treatment of patients with ovarian cancers. In some studies, co-expression of other growth factor receptors has been associated with resistance to therapy with the HER inhibitors. The aim of the present study was to determine the relative expression, cellular location, and prognostic significance of HER-family members, the EGFR mutant (EGFRvIII) c-MET, IGF-1R and the cancer stem cell biomarker CD44 in 60 patients with FIGO stage III and IV ovarian cancer. At cut off >5% of tumour cells with positive staining, 62%, 59%, 65% and 45% of the cases were EGFR, HER-2, HER-3 and HER-4 positive, and 3%, 22% and 48.3% of the cases were positive for EGFRvIII, c-MET, and CD44 respectively. Interestingly, 23% co-expressed all four members of the HER family. On univariate analysis, only EGFR staining at >50% of tumour cells (HR = 3.57, p = 0.038) and CD44 staining at 3+ intensity (HR = 7.99, p = 0.004) were associated with a poorer overall survival. EGFR expression (HR = 2.83, p = 0.019) and its co-expression with HER-2, HER-3, HER-2/HER-3, and c-MET were all associated with poorer disease-free survival. Our results suggest co-expression of the HER-family members is common in Stage III and IV ovarian cancer patients. Further studies on the prognostic significance and predictive value of all HER family member proteins for the response to treatment with various forms of the HER inhibitors are warranted.
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Tsuboi S, Jin T. Recombinant Protein (Luciferase-IgG Binding Domain) Conjugated Quantum Dots for BRET-Coupled Near-Infrared Imaging of Epidermal Growth Factor Receptors. Bioconjug Chem 2018. [DOI: 10.1021/acs.bioconjchem.8b00149] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Setsuko Tsuboi
- Quantitative Biology Center, RIKEN, Furuedai 6-2-3, Suita, Osaka 565-0874, Japan
| | - Takashi Jin
- Quantitative Biology Center, RIKEN, Furuedai 6-2-3, Suita, Osaka 565-0874, Japan
- Graduate School of Frontier Biosciences, Osaka University, Yamada-oka 2-1, Suita, Osaka 565-0871, Japan
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Puvanenthiran S, Essapen S, Seddon AM, Modjtahedi H. Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs. Int J Oncol 2016; 49:1825-1838. [PMID: 27599579 PMCID: PMC5063458 DOI: 10.3892/ijo.2016.3678] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/22/2016] [Indexed: 12/30/2022] Open
Abstract
Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2). Finally, of the TKIs, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. We did not find any significant association between the expression of putative ovarian CSC marker, HER family members, c-MET, ALK, and IGF-IR and the response to the irreversible HER TKIs. Our results support the need for further investigations of the therapeutic potential of these irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members in ovarian cancer.
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Affiliation(s)
- Soozana Puvanenthiran
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
| | - Sharadah Essapen
- St Luke's Cancer Centre, Royal Surrey County Hospital, Guildford GU2 7XX, UK
| | - Alan M Seddon
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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Guo M, Luo G, Liu C, Cheng H, Lu Y, Jin K, Liu Z, Long J, Liu L, Xu J, Huang D, Ni Q, Yu X. The Prognostic and Predictive Role of Epidermal Growth Factor Receptor in Surgical Resected Pancreatic Cancer. Int J Mol Sci 2016; 17:1090. [PMID: 27399694 PMCID: PMC4964466 DOI: 10.3390/ijms17071090] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 06/28/2016] [Accepted: 07/01/2016] [Indexed: 12/28/2022] Open
Abstract
The data regarding the prognostic significance of EGFR (epidermal growth factor receptor) expression and adjuvant therapy in patients with resected pancreatic cancer are insufficient. We retrospectively investigated EGFR status in 357 resected PDAC (pancreatic duct adenocarcinoma) patients using tissue immunohistochemistry and validated the possible role of EGFR expression in predicting prognosis. The analysis was based on excluding the multiple confounding parameters. A negative association was found between overall EGFR status and postoperative survival (p = 0.986). Remarkably, adjuvant chemotherapy and radiotherapy were significantly associated with favorable postoperative survival, which prolonged median overall survival (OS) for 5.8 and 10.2 months (p = 0.009 and p = 0.006, respectively). Kaplan-Meier analysis showed that adjuvant chemotherapy correlated with an obvious survival benefit in the EGFR-positive subgroup rather than in the EGFR-negative subgroup. In the subgroup analyses, chemotherapy was highly associated with increased postoperative survival in the EGFR-negative subgroup (p = 0.002), and radiotherapy had a significant survival benefit in the EGFR-positive subgroup (p = 0.029). This study demonstrated that EGFR expression is not correlated with outcome in resected pancreatic cancer patients. Adjuvant chemotherapy and radiotherapy were significantly associated with improved survival in contrary EGFR expressing subgroup. Further studies of EGFR as a potential target for pancreatic cancer treatment are warranted.
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Affiliation(s)
- Meng Guo
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Guopei Luo
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Chen Liu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - He Cheng
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Yu Lu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Kaizhou Jin
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Zuqiang Liu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Jiang Long
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Liang Liu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Jin Xu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Dan Huang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
| | - Quanxing Ni
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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IOANNOU NIKOLAOS, SEDDON ALANM, DALGLEISH ANGUS, MACKINTOSH DAVID, SOLCA FLAVIO, MODJTAHEDI HELMOUT. Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition. Int J Oncol 2016; 48:908-18. [PMID: 26781210 PMCID: PMC4750538 DOI: 10.3892/ijo.2016.3320] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 11/06/2015] [Indexed: 12/13/2022] Open
Abstract
Drug-resistance is a major contributing factor for the poor prognosis in patients with pancreatic cancer. We have shown previously that the irreversible ErbB family blocker afatinib, is more effective than the reversible EGFR tyrosine kinase inhibitor erlotinib in inhibiting the growth of human pancreatic cancer cells. The aim of this study was to develop human pancreatic cancer cell (BxPc3) variants with acquired resistance to treatment with gemcitabine, afatinib, or erlotinib, and to investigate the molecular changes that accompany the acquisition of a drug-resistant phenotype. We also investigated the therapeutic potential of various agents in the treatment of such drug-resistant variants. Three variant forms of BxPc3 cells with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) were developed following treatment with increasing doses of such drugs. The expression level, mutational and phosphorylation status of various growth factor receptors and downstream cell signaling molecules were determined by FACS, human phopsho-RTK array, and western blot analysis while the sulforhodamine B assay was used for determining the effect of various agents on the growth of such tumours. We found that all three BxPc3 variants with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) also become less sensitive to treatment with the two other agents. Acquisition of resistance to these agents was accompanied by upregulation of p-c-MET, p-STAT3, CD44, increased autocrine production of EGFR ligand amphiregulin and differential activation status of EGFR tyrosine residues as well as downregulation of total and p-SRC. Of all therapeutic interventions examined, including the addition of an anti-EGFR antibody ICR62, an anti-CD44 monoclonal antibody, and of STAT3 or c-MET inhibitors, only treatment with the STAT3 inhibitor Stattic produced a higher growth inhibitory effect in all three drug-resistant variants. In addition, treatment with a combination of afatinib with either c-MET inhibitor Crizotinib or Stattic resulted in an additive or synergistic growth inhibition in all three variants. Our results suggest that activation of STAT3 may play an important role in the acquisition of resistance to gemcitabine and HER inhibitors in pancreatic cancer and warrant further studies on the therapeutic potential of STAT3 inhibitors in such a setting.
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Affiliation(s)
- NIKOLAOS IOANNOU
- School of Life Science, Pharmacy and Chemistry, Kingston University London, Kingston
| | - ALAN M. SEDDON
- School of Life Science, Pharmacy and Chemistry, Kingston University London, Kingston
| | - ANGUS DALGLEISH
- Department of Cellular and Molecular Medicine, St George's University of London, London, UK
| | - DAVID MACKINTOSH
- School of Life Science, Pharmacy and Chemistry, Kingston University London, Kingston
| | - FLAVIO SOLCA
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - HELMOUT MODJTAHEDI
- School of Life Science, Pharmacy and Chemistry, Kingston University London, Kingston
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Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers. Br J Cancer 2015; 113:1010-9. [PMID: 26372697 PMCID: PMC4651123 DOI: 10.1038/bjc.2015.319] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 06/15/2015] [Accepted: 08/12/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The human epidermal growth factor receptor (EGFR) is an important target for cancer treatment. Currently, only the EGFR antibodies cetuximab and panitumumab are approved for the treatment of patients with colorectal cancer. However, a major clinical challenge is a short-term response owing to development of acquired resistance during the course of the treatment. METHODS In this study, we investigated the molecular mechanisms underlying development of acquired resistance in DiFi colorectal cancer cells to the anti-EGFR mAb ICR62 (termed DiFi62) and to the small molecule tyrosine kinase inhibitor (TKI) gefitinib (termed DiFiG) using a range of techniques. RESULTS Compared with the findings from parental DiFi and DiFiG cells, development of acquired resistance to anti-EGFR mAb ICR62 in DiFi62 cells was accompanied by an increase in cell surface EGFR and increased phosphorylation of HER-2 and HER-3. Interestingly, DiFi62 cells also acquired resistance to treatment with anti-EGFR mAbs cetuximab and ICR61, which bind to other distinct epitopes on the extracellular domain of EGFR, but these cells remained equally sensitive as the parental cells to treatment with pan-HER inhibitors such as afatinib. CONCLUSIONS Our results provide a novel mechanistic insight into the development of acquired resistance to EGFR antibody-based therapy in colorectal cancer cells and justify further investigations on the therapeutic benefits of pan-HER family inhibitors in the treatment of colorectal cancer patients once acquired resistance to EGFR antibody-based therapy is developed.
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Rao S, Larroque-Lombard AL, Peyrard L, Thauvin C, Rachid Z, Williams C, Jean-Claude BJ. Target modulation by a kinase inhibitor engineered to induce a tandem blockade of the epidermal growth factor receptor (EGFR) and c-Src: the concept of type III combi-targeting. PLoS One 2015; 10:e0117215. [PMID: 25658745 PMCID: PMC4414309 DOI: 10.1371/journal.pone.0117215] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 12/19/2014] [Indexed: 12/16/2022] Open
Abstract
Cancer cells are characterized by a complex network of interrelated and compensatory signaling driven by multiple kinases that reduce their sensitivity to targeted therapy. Therefore, strategies directed at inhibiting two or more kinases are required to robustly block the growth of refractory tumour cells. Here we report on a novel strategy to promote sustained inhibition of two oncogenic kinases (Kin-1 and Kin-2) by designing a molecule K1-K2, termed "combi-molecule", to induce a tandem blockade of Kin-1 and Kin-2, as an intact structure and to be further hydrolyzed to two inhibitors K1 and K2 directed at Kin-1 and Kin-2, respectively. We chose to target EGFR (Kin-1) and c-Src (Kin-2), two tyrosine kinases known to synergize to promote tumour growth and progression. Variation of K1-K2 linkers led to AL776, our first optimized EGFR-c-Src targeting prototype. Here we showed that: (a) AL776 blocked EGFR and c-Src as an intact structure using an in vitro kinase assay (IC50 EGFR = 0.12 μM and IC50 c-Src = 3 nM), (b) it could release K1 (AL621, a nanomolar EGFR inhibitor) and K2 (dasatinib, a clinically approved Abl/c-Src inhibitor) by hydrolytic cleavage both in vitro and in vivo, (c) it could robustly inhibit phosphorylation of EGFR and c-Src (0.25-1 μM) in cells, (d) it induced 2-4 fold stronger growth inhibition than gefitinib or dasatinib and apoptosis at concentrations as low as 1 μM, and, (e) blocked motility and invasion at sub-micromolar doses in the highly invasive 4T1 and MDA-MB-231 cells. Despite its size (MW = 1032), AL776 blocked phosphorylation of EGFR and c-Src in 4T1 tumours in vivo. We now term this new targeting model consisting of designing a kinase inhibitor K1-K2 to target Kin-1 and Kin-2, and to further release two inhibitors K1 and K2 of the latter kinases, "type III combi-targeting".
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Affiliation(s)
- Suman Rao
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
| | - Anne-Laure Larroque-Lombard
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
| | - Lisa Peyrard
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
| | - Cédric Thauvin
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
| | - Zakaria Rachid
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
| | - Christopher Williams
- Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910,
Montreal, QC, H3A 2R7 Canada
| | - Bertrand J. Jean-Claude
- Cancer Drug Research Laboratory, Department of Medicine, Division of
Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687
Pine Avenue West Rm M7.19, Montreal, Quebec, H3A 1A1 Canada
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12
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Dal Lin C, Tona F, Osto E. Coronary Microvascular Function and Beyond: The Crosstalk between Hormones, Cytokines, and Neurotransmitters. Int J Endocrinol 2015; 2015:312848. [PMID: 26124827 PMCID: PMC4466475 DOI: 10.1155/2015/312848] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 03/10/2015] [Accepted: 03/16/2015] [Indexed: 01/18/2023] Open
Abstract
Beyond its hemodynamic function, the heart also acts as a neuroendocrine and immunoregulatory organ. A dynamic communication between the heart and other organs takes place constantly to maintain cardiovascular homeostasis. The current understanding highlights the importance of the endocrine, immune, and nervous factors to fine-tune the crosstalk of the cardiovascular system with the entire body. Once disrupted, this complex interorgan communication may promote the onset and the progression of cardiovascular diseases. Thus, expanding our knowledge on how these factors influence the cardiovascular system can lead to novel therapeutic strategies to improve patient care. In the present paper, we review novel concepts on the role of endocrine, immune, and nervous factors in the modulation of microvascular coronary function.
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Affiliation(s)
- Carlo Dal Lin
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Via Giustiniani 2, 35100 Padua, Italy
| | - Francesco Tona
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Via Giustiniani 2, 35100 Padua, Italy
| | - Elena Osto
- Centre for Molecular Cardiology, University of Zurich and University Heart Center, Department of Cardiology, University Hospital, Raemistrasse 100, 8091 Zurich, Switzerland
- *Elena Osto:
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13
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Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts. Neoplasia 2014; 16:105-14. [PMID: 24709418 DOI: 10.1593/neo.14182] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 01/23/2014] [Accepted: 01/23/2014] [Indexed: 12/11/2022] Open
Abstract
We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al.: (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem288, 26879-26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.
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14
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Modjtahedi H, Cho BC, Michel MC, Solca F. A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2014; 387:505-21. [PMID: 24643470 PMCID: PMC4019832 DOI: 10.1007/s00210-014-0967-3] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 02/19/2014] [Indexed: 01/07/2023]
Abstract
Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.
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Affiliation(s)
- Helmout Modjtahedi
- School of Life Science, Faculty of Science, Engineering and Computing, Kingston University London, Kingston upon Thames, UK
| | - Byoung Chul Cho
- Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Martin C. Michel
- Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany
- Department of Regional Medicine and Scientific Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Flavio Solca
- Department of Pharmacology, Boehringer Ingelheim RCV GmbH & Co. KG, Doktor-Böhringer Gasse 5-11, 1120 Vienna, Austria
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15
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Barrett CW, Singh K, Motley AK, Lintel MK, Matafonova E, Bradley AM, Ning W, Poindexter SV, Parang B, Reddy VK, Chaturvedi R, Fingleton BM, Washington MK, Wilson KT, Davies SS, Hill KE, Burk RF, Williams CS. Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS One 2013; 8:e67845. [PMID: 23861820 PMCID: PMC3701622 DOI: 10.1371/journal.pone.0067845] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 05/21/2013] [Indexed: 12/13/2022] Open
Abstract
Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
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Affiliation(s)
- Caitlyn W. Barrett
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Kshipra Singh
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, United States of America
| | - Amy K. Motley
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Mary K. Lintel
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Elena Matafonova
- Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Amber M. Bradley
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Wei Ning
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Shenika V. Poindexter
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Bobak Parang
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Vishruth K. Reddy
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Rupesh Chaturvedi
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, United States of America
| | - Barbara M. Fingleton
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Mary K. Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Keith T. Wilson
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, United States of America
| | - Sean S. Davies
- Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Kristina E. Hill
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Raymond F. Burk
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Christopher S. Williams
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, United States of America
- * E-mail:
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16
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Worsham MJ, Chen KM, Ghanem T, Stephen JK, Divine G. Epigenetic modulation of signal transduction pathways in HPV-associated HNSCC. Otolaryngol Head Neck Surg 2013; 149:409-16. [PMID: 23736812 DOI: 10.1177/0194599813490895] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Human papilloma virus (HPV) positive and HPV negative head and neck squamous cell cancer (HNSCC) are biologically distinct with a prognostic advantage for HPV positive patients compared to HPV negative cases. DNA promoter methylation is central to human diseases such as cancer, including HNSCC, with reported genome-wide hypomethylaton and promoter hypermethylation in HPV positive HNSCC tumors. The goal of this study was to identify differentially methylated genes in HPV positive versus HPV negative primary HNSCC genomes with clues to signaling networks. STUDY DESIGN Laboratory-based study. SETTING Primary care academic health care system. SUBJECTS AND METHODS DNA from 4 HPV positive and 4 HPV negative freshly frozen primary HNSCC were subject to comprehensive genome-wide methylation profiling. Differentially methylated gene lists were examined using the Signal Transduction Pathways (canonical) filter in the Genomatix Pathway System (GePS). RESULTS Twofold methylation differences were observed between HPV positive and HPV negative cases for 1168 genes. Pathway analysis applied to investigate the biological role of the 1168 differentially methylated genes revealed 8 signal transduction pathways forming a network of 66 genes, of which 62% are hypermethylated. CONCLUSION Our study reveals a predominant hypermethylation profile for genes in signal transduction pathways of HPV positive HNSCC tumor genomes. Because signaling events in the cell play a critical role in the execution of key biological functions, insights into how complex cellular signaling cascades and networks may be programmed in HNSCC are likely to be critical in the development of new biological agents designed to hit multiple targets.
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Affiliation(s)
- Maria J Worsham
- Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, Michigan 48202, USA.
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17
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Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H. Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells. BMC Cancer 2013; 13:41. [PMID: 23367880 PMCID: PMC3598209 DOI: 10.1186/1471-2407-13-41] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 01/28/2013] [Indexed: 12/12/2022] Open
Abstract
Background Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells. Methods The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis. Results All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 μM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells. Conclusion Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers.
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Affiliation(s)
- Nikolaos Ioannou
- School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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Worsham MJ, Ali H, Dragovic J, Schweitzer VP. Molecular characterization of head and neck cancer: how close to personalized targeted therapy? Mol Diagn Ther 2012; 16:209-22. [PMID: 22873739 DOI: 10.2165/11635330-000000000-00000] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Molecular targeted therapy in head and neck squamous cell carcinoma (HNSCC) continues to make strides, and holds much promise. Cetuximab remains the sole US FDA-approved molecular targeted therapy available for HNSCC, though several new biologic agents targeting the epidermal growth factor receptor (EGFR) and other pathways are currently in the regulatory approval pipeline. While targeted therapies have the potential to be personalized, their current use in HNSCC is not personalized. This is illustrated for EGFR-targeted drugs, where EGFR as a molecular target has yet to be individualized for HNSCC. Future research needs to identify factors that correlate with response (or lack of one) and the underlying genotype-phenotype relationship that dictates this response. Comprehensive exploration of genetic and epigenetic landscapes in HNSCC is opening new frontiers to further enlighten and mechanistically inform newer as well as existing molecular targets, and to set a course for eventually translating these discoveries into therapies for patients. This opinion offers a snapshot of the evolution of molecular subtyping in HNSCC and its current clinical applicability, as well as new emergent paradigms with implications for controlling this disease in the future.
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Affiliation(s)
- Maria J Worsham
- Department of OtolaryngologyHead and Neck Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
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Modjtahedi H, Khelwatty SA, Kirk RS, Seddon AM, Essapen S, Del Vecchio CA, Wong AJ, Eccles S. Immunohistochemical discrimination of wild-type EGFR from EGFRvIII in fixed tumour specimens using anti-EGFR mAbs ICR9 and ICR10. Br J Cancer 2012; 106:883-8. [PMID: 22315050 PMCID: PMC3305949 DOI: 10.1038/bjc.2012.27] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Background: The human epidermal growth factor receptor (EGFR) is an important therapeutic target in oncology, and three different types of EGFR inhibitors have been approved for the treatment of cancer patients. However, there has been no clear association between the expression levels of EGFR protein in the tumours determined by the FDA-approved EGFR PharmDx kit (Dako) or other standard anti-EGFR antibodies and the response to the EGFR inhibitors. Method: In this study, we investigated the potential of our anti-EGFR monoclonal antibodies (mAbs; ICR9, ICR10, ICR16) for immunohistochemical diagnosis of wild-type EGFR and/or the type-III deletion mutant form of EGFR (EGFRvIII) in formalin-fixed, paraffin-embedded human tumour specimens. Results: We found that the anti-EGFR mAb in the EGFR PharmDx kit stained both wild-type and EGFRvIII-expressing cells in formalin-fixed, paraffin-embedded sections. This pattern of EGFR immunostaining was also found with our anti-EGFR mAb ICR16. In contrast, mAbs ICR10 and ICR9 were specific for the wild-type EGFR. Conclusion: We conclude that mAbs ICR9 and ICR10 are ideal tools for investigating the expression patterns of wild-type EGFR protein in tumour specimens using immunohistochemistry, and to determine their prognostic significance, as well as predictive value for response to therapy with EGFR antibodies.
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Affiliation(s)
- H Modjtahedi
- School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK.
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20
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Ioannou N, Dalgleish AG, Seddon AM, Mackintosh D, Guertler U, Solca F, Modjtahedi H. Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. Br J Cancer 2011; 105:1554-62. [PMID: 21970876 PMCID: PMC3242519 DOI: 10.1038/bjc.2011.396] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker. METHODS We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively. RESULTS At 200 nM, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC(50) values of 11 and 1200 nM. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth. CONCLUSION The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.
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Affiliation(s)
- N Ioannou
- School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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Michel RB, Castillo ME, Andrews PM, Mattes MJ. In vitro toxicity of A-431 carcinoma cells with antibodies to epidermal growth factor receptor and epithelial glycoprotein-1 conjugated to radionuclides emitting low-energy electrons. Clin Cancer Res 2005; 10:5957-66. [PMID: 15355929 DOI: 10.1158/1078-0432.ccr-03-0465] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The ability of antibodies (Abs) conjugated to radionuclides emitting low-energy electrons to specifically kill nonadherent lymphoma target cells in vitro was demonstrated previously. This study extends this work to adherent carcinoma cells. The fact that these cells are spread out on plastic can potentially make it more difficult to deliver radiation to the nucleus from decays in the cytoplasm or on the cell surface. EXPERIMENTAL DESIGN The Abs tested were anti-epidermal growth factor receptor and anti-epithelial glycoprotein-1, conjugated to indium-111 or iodine-125, which emit low-energy Auger and conversion electrons. Conjugates of the beta-particle emitter, iodine-131, also were tested, for comparison. Abs were incubated with the cells for 2 days, and then the treated cells were assayed for colony-forming units. The radiation dose delivered to the nucleus was calculated from the cumulative decays per cell. RESULTS With conjugates of (111)In, very potent killing was obtained with both of the Abs, with 100% kill (approximately 4-5 logs) even at subsaturating Ab concentrations. Lower levels of kill were obtained with (125)I or (131)I conjugates. Conjugates with (131)I, a beta-particle emitter, produced greater nonspecific toxicity. The greater potency of (111)In could be attributed to the higher specific activity that was obtained routinely with this radiolabel, up to 70 mCi/mg. Uptake of radioactivity peaked at approximately 200 cpm per cell. Dosimetry calculations, using subcellular S values, demonstrated that the toxicity observed was consistent with the amount of radiation delivered to the nucleus. CONCLUSIONS These results are similar to previous results obtained with B lymphoma cells and indicate that this approach is applicable to a wide range of tumor types. Radionuclides emitting low-energy electrons are effective at killing target cells with relatively little nonspecific toxicity, if sufficient activity is delivered to the cell. Most Abs to high-density cell surface antigens would probably be effective.
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Affiliation(s)
- Rosana B Michel
- Center for Molecular Medicine and Immunology, Belleville, New Jersey, USA
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22
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Banerjee R, Rachid Z, Qiu Q, McNamee JP, Tari AM, Jean-Claude BJ. Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line. Br J Cancer 2004; 91:1066-73. [PMID: 15365562 PMCID: PMC2747684 DOI: 10.1038/sj.bjc.6602098] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed ‘Cascade-release targeting’ that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene expression, (d) RB24 induced irreversible cell growth inhibition with a 100-fold greater potency than Temodal™, a clinical methyltriazene. The pronounced growth inhibitory potency of RB24 was attributed to its ability to simultaneously damage DNA and irreversibly block EGFR TK activity.
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Affiliation(s)
- R Banerjee
- Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, Canada H3A 1A1
| | - Z Rachid
- Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, Canada H3A 1A1
| | - Q Qiu
- Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, Canada H3A 1A1
| | - J P McNamee
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada K1A 1C1
| | - A M Tari
- The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - B J Jean-Claude
- Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, Canada H3A 1A1
- Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, Canada H3A 1A1. E-mail:
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23
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Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabárbara P, Bonomi P. Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol 2004; 22:3238-47. [PMID: 15310767 DOI: 10.1200/jco.2004.11.057] [Citation(s) in RCA: 824] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Erlotinib is a highly specific epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. This phase II study of erlotinib in patients with HER1/EGFR-expressing non-small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response, survival, and symptom improvement. PATIENTS AND METHODS Fifty-seven patients received an oral, continuous daily dose of 150 mg of erlotinib. Assessments of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, supplemented with a lung cancer module, Quality of Life Questionnaire LC13, was used to measure health-related quality of life. Additional analyses were performed to identify predictors of response and survival. RESULTS The objective response rate was 12.3% (95% CI, 5.1% to 23.7%). Responses were observed regardless of type or number of prior chemotherapy regimens. Median survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%). Erlotinib therapy was associated with tumor-related symptom improvement. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. One patient experienced toxicity consisting of severe grade 3 rash and diarrhea. Time since diagnosis and good performance status were significant predictors of survival in a multivariate Cox proportional hazards model, whereas HER1/EGFR staining intensity was not. Additionally, survival correlated with the occurrence and severity of rash. CONCLUSION Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.
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Affiliation(s)
- Román Pérez-Soler
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY 10467, USA.
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24
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Vega J, Ke S, Fan Z, Wallace S, Charsangavej C, Li C. Targeting doxorubicin to epidermal growth factor receptors by site-specific conjugation of C225 to poly(L-glutamic acid) through a polyethylene glycol spacer. Pharm Res 2003; 20:826-32. [PMID: 12751641 DOI: 10.1023/a:1023454107190] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
PURPOSE Targeted delivery of chemotherapeutic agents through antibody-polymer conjugates has met with limited success. One of the limiting factors is the loss of antibody's binding affinity upon conjugation with polymeric carriers because of lack of control over the number and site of attachment. This study aims to synthesize monovalent polymeric immunoconjugates through site-specific conjugation and to evaluate the in vitro binding activities of the resulting construct. METHODS Antibody C225 against epidermal growth factor receptors was coupled to the terminus of a doxorubicin-bound block copolymer, poly(L-glutamic acid)-co-polyethylene glycol (PG-PEG). Western blot analysis, confocal fluorescent microscopy, and cytotoxicity assay were performed to confirm the specific binding of C225-PEG-PG-Dox to EGFR. RESULTS C225 was conjugated to PEG-PG-doxorubicin conjugates by reacting sulfhydryl group introduced to C225 with vinylsulfone group introduced at the terminus of PEG-PG block copolymer. Polymeric immunoconjugate C225-PEG-PG-Dox, but not control (i.e., conjugate without antibody), selectively bound to human vulvar squamous carcinoma A431 cells that overexpress epidermal growth factor receptors. Receptor-mediated uptake of C225-PEG-PG-Dox occurred rapidly (within 5 min), whereas nonspecific uptake of PEG-PG-Dox required an extended period of time (24 h) to internalize. Binding of C225-PEG-PG-Dox to A431 cells could be blocked by pretreatment with C225 antibody. C225-PEG-PG-Dox was more potent than free doxrubicin in inhibiting the growth of A431 cells after a 6-h exposure period. CONCLUSION Site-specific conjugation of a monoclonal antibody to the terminus of a polymeric carrier enhances receptor-mediated delivery of anticancer agents.
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Affiliation(s)
- Javier Vega
- Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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25
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Yang W, Barth RF, Leveille R, Adams DM, Ciesielski M, Fenstermaker RA, Capala J. Evaluation of systemically administered radiolabeled epidermal growth factor as a brain tumor targeting agent. J Neurooncol 2001; 55:19-28. [PMID: 11804279 DOI: 10.1023/a:1013017821166] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We have previously reported a method for labeling epidermal growth factor (EGF) with technetium-99m and have shown that 99mTc-EGF localized in EGF receptor (R) positive intracerebral C6EGFR rat gliomas following intratumoral (i.t.) injection of the radioligand. In the present study, we have evaluated the potential use of 99mTc-EGF as a tumor targeting agent after systemic administration to Fischer rats bearing intracerebral implants of C6EGFRgliomas. Radiolocalization was determined following intravenous (i.v.) or intracarotid (i.c.) injection with or without hyperosmotic mannitol induced disruption of the blood-brain barrier (BBB-D). As determined by gamma-scintillation counting, 4 h after i.c. injection of 99mTc-EGF, 0.34% of the injected dose per gram (% ID/g) was localized in C6EGFR tumors. which expressed 10(5)-10(6) EGFR sites per cell, compared to 0.07% ID/g in animals bearing C6 wildtype gliomas, which do not express EGFR. The corresponding tumor to brain ratios were 5.6 and 1.6, respectively. Tumors could be visualized by external gamma-scintigraphy in rats bearing C6EGFR but not C6 wildtype gliomas, thereby establishing that radiolocalization was dependent upon receptor expression. Intracarotid administration of 99mTc-EGF significantly increased tumor uptake compared to i.v. injection (0.34 vs 0.14% ID/g, p < 0.04). BBB-D disruption, followed by i.c. injection of 99mTc-EGF, however, did not significantly enhance tumor uptake compared to i.c. injection without BBB-D (0.45% vs 0.34% ID/g, p > 0.1). The uptake of 99mTc-EGF was approximately 4-9% ID/g in the liver and 12-20% ID/g in the kidneys after i.c. or i.v. administration. External gamma-scintigraphy of regions of interest over the liver and kidneys revealed that approximately 70-80% of the whole body radioactivity accumulated in these organs, and only 0.47-0.83% in the tumor following i.v. or i.c. administration of 99m9Tc-EGF. Our study has demonstrated that EGF can be used as a specific targeting agent for EGFR (+) rat brain tumors. However, it is unlikely that systemic injection of EGF-based bioconjugates can deliver sufficient amounts of the ligand to brain tumors for therapeutic purposes and direct delivery by means of either intratumoral injection or a variant of it such as convection enhanced delivery will be required.
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Affiliation(s)
- W Yang
- Department of Pathology, The Ohio State University, Columbus 43210, USA
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26
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Radinsky R. Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev 1995; 14:323-38. [PMID: 8821093 DOI: 10.1007/bf00690601] [Citation(s) in RCA: 80] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The mechanistic basis of a metastatic cell's ability to proliferate in the parenchyma of certain organs and develop organ-specific metastases is under intense investigation. Signals from paracrine or autocrine pathways, alone or in combination, may regulate tumor cell proliferation with the eventual outcome dependent on the net balance of stimulatory and inhibitory factors. This article summarizes recent reports from our laboratory and others demonstrating that the organ microenvironment can profoundly influence the pattern of gene expression and the biological phenotype of metastatic tumor cells, including induction of melanocyte stimulating hormone receptor and production of melanin, regulation of terminal differentiation and apoptosis, resistance to chemotherapy, and regulation of growth at the organ-specific metastatic site. These recent data from both murine and human tumor models support the concept that the microenvironment of different organs can influence the pattern of gene expression and hence the phenotype of tumor cells at different steps of the metastatic process. These findings have obvious implications for the therapy of neoplasms in general and metastases in particular.
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Affiliation(s)
- R Radinsky
- Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA
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Kunkel MW, Hook KE, Howard CT, Przybranowski S, Roberts BJ, Elliott WL, Leopold WR. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs 1995; 13:295-302. [PMID: 8824347 DOI: 10.1007/bf00873135] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PD153035 is a potent (Ki = 6 pm) and specific inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase that suppresses tyrosine phosphorylation of the EGF receptor in A431 cells at nanomolar concentrations in cell culture. We have examined the pharmacokinetics of this compound and its ability to rapidly suppress phosphorylation of the EGF receptor in A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 microM within 15 minutes. While the plasma levels of PD153035 fell below 1 microM by 3 hours, in the tumors it remained at micromolar concentrations for at least 12 hours. The tyrosine phosphorylation of the EGF receptor was rapidly suppressed by 80-90% in the tumors. However receptor phosphorylation returned to control levels after 3 hours despite the continued presence of the drug at concentrations which, based on previous in vitro results, were predicted to maintain inhibition. EGF-stimulated tyrosine kinase activity in tumor extracts was decreased and recovered in parallel with the effects of PD153035 on receptor phosphorylation though the activity had reached only about half of the control activity after three hours. These results demonstrate the potential for using small molecule inhibitors to inhibit the EGF receptor tyrosine kinase in vivo, though a fair evaluation of their potential anti-cancer activity will have to wait for solutions to problems with sustained delivery which may allow us to maintain suppression of EGF receptor phosphorylation.
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Affiliation(s)
- M W Kunkel
- Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Department of Cancer Research, Ann Arbor, MI 48105, USA
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