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Gasparri AM, Pocaterra A, Colombo B, Taiè G, Gnasso C, Gori A, Pozzi F, Smith A, Magni F, Ugolini A, Doglio M, Bonini MC, Mondino A, Corti A, Curnis F. Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth. J Exp Clin Cancer Res 2025; 44:88. [PMID: 40055773 PMCID: PMC11889887 DOI: 10.1186/s13046-025-03352-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many solid tumors, can promote the activation of transforming growth factor-β (TGFβ), a potent immunosuppressive cytokine, by interacting with the RGD sequence of the latency-associated peptide (LAP)/TGFβ complex. We have previously described a chromogranin A-derived peptide, called "peptide 5a", which recognizes the RGD-binding site of both αvβ6 and αvβ8 with high affinity and selectivity, and efficiently accumulates in αvβ6- or αvβ8-positive tumors. This study aims to demonstrate that peptide 5a can inhibit TGFβ activation in tumors and suppress tumor growth. METHODS Peptide 5a was chemically coupled to human serum albumin (HSA) to prolong its plasma half-life. The integrin recognition properties of this conjugate (called 5a-HSA) and its capability to block TGFβ activation by αvβ6+ and/or αvβ8+ cancer cells or by regulatory T cells (Tregs) were tested in vitro. The in vivo anti-tumor effects of 5a-HSA, alone and in combination with S-NGR-TNF (a vessel-targeted derivative of tumor necrosis factor-a), were investigated in various murine tumor models, including pancreatic ductal adenocarcinoma, fibrosarcoma, prostate cancer, and mammary adenocarcinoma. RESULTS In vitro assays showed that peptide 5a coupled to HSA maintains its capability of recognizing αvβ6 and αvβ8 with high affinity and selectivity and inhibits TGFβ activation mediated by αvβ6+ and/or αvβ8+ cancer cells, as well as by αvβ8+ Tregs. In vivo studies showed that systemic administration of 5a-HSA to tumor-bearing mice can reduce TGFβ signaling in neoplastic tissues and promote CD8-dependent anti-tumor responses. Combination therapy studies showed that 5a-HSA can enhance the anti-tumor activity of S-NGR-TNF, leading to tumor eradication. CONCLUSION Peptide 5a is an efficient tumor-homing inhibitor of αvβ6- and αvβ8-integrin that after coupling to HSA, can be used as a drug to block integrin-dependent TGFβ activation in tumors and promote immunotherapeutic responses.
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Affiliation(s)
- Anna Maria Gasparri
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Arianna Pocaterra
- Lymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Taiè
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Chiara Gnasso
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Gori
- Istituto di Scienze e Tecnologie Chimiche (SCITEC-CNR), National Research Council of Italy, Milan, Italy
| | - Federica Pozzi
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Andrew Smith
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Milan, Italy
| | - Fulvio Magni
- Department of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-Bicocca, Milan, Italy
| | - Alessia Ugolini
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Matteo Doglio
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Chiara Bonini
- Experimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Anna Mondino
- Lymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
| | - Flavio Curnis
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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Maldonado H, Dreger M, Bedgood LD, Kyriakou T, Wolanska KI, Rigby ME, Marotta VE, Webster JM, Wang J, Rusilowicz-Jones EV, Marshall JF, Coulson JM, Macpherson IR, Hurlstone A, Morgan MR. A trafficking regulatory subnetwork governs α Vβ 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. SCIENCE ADVANCES 2024; 10:eadk9944. [PMID: 39630893 PMCID: PMC11616693 DOI: 10.1126/sciadv.adk9944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 10/31/2024] [Indexed: 12/07/2024]
Abstract
HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We identify an αVβ6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αVβ6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between αVβ6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.
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Affiliation(s)
- Horacio Maldonado
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Marcel Dreger
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Lara D. Bedgood
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Theano Kyriakou
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Katarzyna I. Wolanska
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Megan E. Rigby
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Valeria E. Marotta
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Justine M. Webster
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Jun Wang
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Emma V. Rusilowicz-Jones
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - John F. Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Judy M. Coulson
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Iain R. Macpherson
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK
| | - Adam Hurlstone
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Mark R. Morgan
- Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
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Shen YQ, Sun L, Wang SM, Zheng XY, Xu R. Exosomal integrins in tumor progression, treatment and clinical prediction (Review). Int J Oncol 2024; 65:118. [PMID: 39540373 PMCID: PMC11575930 DOI: 10.3892/ijo.2024.5706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Integrins are a large family of cell adhesion molecules involved in tumor cell differentiation, migration, proliferation and neovascularization. Tumor cell‑derived exosomes carry a large number of integrins, which are closely associated with tumor progression. As crucial mediators of intercellular communication, exosomal integrins have gained attention in the field of cancer biology. The present review examined the regulatory mechanisms of exosomal integrins in tumor cell proliferation, migration and invasion, and emphasized their notable roles in tumor initiation and progression. The potential of exosomal integrins as drug delivery systems in cancer treatment was explored. Additionally, the potential of exosomal integrins in clinical tumor prediction was considered, while summarizing their applications in diagnosis, prognosis assessment and treatment response prediction. Thus, the present review aimed to provide guidance and insights for future basic research and the clinical translation of exosomal integrins. The study of exosomal integrins is poised to offer new perspectives and methods for precise cancer treatment and clinical prediction.
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Affiliation(s)
- Yu-Qing Shen
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, Anhui 230032, P.R. China
| | - Lei Sun
- Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Shi-Ming Wang
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, Anhui 230032, P.R. China
| | - Xian-Yu Zheng
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, Anhui 230032, P.R. China
| | - Rui Xu
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, Anhui 230032, P.R. China
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Liu L, Soler J, Reckamp KL, Sankar K. Emerging Targets in Non-Small Cell Lung Cancer. Int J Mol Sci 2024; 25:10046. [PMID: 39337530 PMCID: PMC11432526 DOI: 10.3390/ijms251810046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mechanisms and molecular pathways for which targeted treatments are currently available. Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC.
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Affiliation(s)
- Louisa Liu
- Samuel-Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Joshua Soler
- Riverside School of Medicine, University of California, Riverside, CA 92521, USA
| | - Karen L Reckamp
- Samuel-Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Kamya Sankar
- Samuel-Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Stangl S, Nguyen NT, Brosch-Lenz J, Šimeček J, Weber WA, Kossatz S, Notni J. Efficiency of succinylated gelatin and amino acid infusions for kidney uptake reduction of radiolabeled αvβ6-integrin targeting peptides: considerations on clinical safety profiles. Eur J Nucl Med Mol Imaging 2024; 51:3191-3201. [PMID: 38717591 PMCID: PMC11369040 DOI: 10.1007/s00259-024-06738-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 04/26/2024] [Indexed: 09/03/2024]
Abstract
PURPOSE 68Ga-Trivehexin is an investigational PET radiopharmaceutical (NCT05799274) targeting αvβ6-integrin for PET imaging of carcinomas. 177Lu-D0301 is a structurally related therapeutic peptide tetramer. However, it showed considerable kidney uptake in rodents, impeding clinical applicability. We therefore evaluated the impact of different kidney protection strategies on the biodistribution of both agents in normal and tumor-bearing mice. METHODS Ex-vivo biodistribution of 68Ga-Trivehexin (90 min p.i.) and 177Lu-D0301 (90 min and 24 h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100 µL of solutions containing 2.5% arginine + 2.5% lysine (Arg/Lys), 4% succinylated gelatin (gelofusine, gelo), or combinations thereof. Arg/Lys was injected either i.p. 30 min before and after the radiopharmaceutical, or i.v. 2 min before the radiopharmaceutical. Gelo was administered either i.v. 2 min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90 min p.i.) and SPECT (24 h p.i.). RESULTS Kidney uptake of 68Ga-Trivehexin in C57BL/6N mice was reduced by 15% (Arg/Lys i.p.), 25% (Arg/Lys i.v.), and 70% (gelo i.v.), 90 min p.i., relative to control. 177Lu-D0301 kidney uptake was reduced by 2% (Arg/Lys i.p.), 41% (Arg/Lys i.v.), 61% (gelo i.v.) and 66% (gelo + Arg/Lys i.v.) 24 h p.i., compared to control. Combination of Arg/Lys and gelo provided no substantial benefit. Gelo furthermore reduced kidney uptake of 177Lu-D0301 by 76% (90 min p.i.) and 85% (24 h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90 min p.i.) or only slightly reduced (15%, 24 h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90 min p.i.) and 2.6 (24 h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex. CONCLUSIONS The kidney uptake of both investigated radiopharmaceuticals was more efficiently reduced by gelofusine (61-85%) than Arg/Lys (25-41%). Gelofusine appears particularly suitable for reducing renal uptake of αvβ6-integrin targeted 177Lu-labeled peptide multimers because its application led to approximately three times higher tumor-to-kidney ratios. Since the incidence of severe adverse events (anaphylaxis) with succinylated gelatin products (reportedly 0.0062-0.038%) is comparable to that of gadolinium-based MRI or iodinated CT contrast agents (0.008% and 0.04%, respectively), clinical use of gelofusine during radioligand therapy appears feasible if similar risk management strategies as for contrast agents are applied.
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Affiliation(s)
- Stefan Stangl
- Department of Nuclear Medicine, University Hospital Klinikum Rechts Der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Nghia Trong Nguyen
- Department of Nuclear Medicine, University Hospital Klinikum Rechts Der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Julia Brosch-Lenz
- Department of Nuclear Medicine, University Hospital Klinikum Rechts Der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | | | - Wolfgang A Weber
- Department of Nuclear Medicine, University Hospital Klinikum Rechts Der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Susanne Kossatz
- Department of Nuclear Medicine, University Hospital Klinikum Rechts Der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
- Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, Technical University of Munich, Munich, Germany.
- Department of Chemistry, School of Natural Sciences, Technical University of Munich, Munich, Germany.
| | - Johannes Notni
- TRIMT GmbH, Radeberg, Germany.
- Institute of Pathology, School of Medicine and Health, Technische Universität München, München, Germany.
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Paulus J, Sewald N. Small molecule- and peptide-drug conjugates addressing integrins: A story of targeted cancer treatment. J Pept Sci 2024; 30:e3561. [PMID: 38382900 DOI: 10.1002/psc.3561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 02/23/2024]
Abstract
Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleavable or non-cleavable linker in peptide-drug conjugates (PDCs) or small molecule-drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody-drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small-molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin αVβ3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin-addressing PDCs and SMDCs while highlighting points of great interest.
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Affiliation(s)
- Jannik Paulus
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
| | - Norbert Sewald
- Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany
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Quigley NG, Zierke MA, Ludwig BS, Richter F, Nguyen NT, Reissig F, Šimeček J, Kossatz S, Notni J. The importance of tyrosines in multimers of cyclic RGD nonapeptides: towards αvβ6-integrin targeted radiotherapeutics. RSC Med Chem 2024; 15:2018-2029. [PMID: 38911160 PMCID: PMC11187563 DOI: 10.1039/d4md00073k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/18/2024] [Indexed: 06/25/2024] Open
Abstract
In a recent paper in this journal (RSC Med. Chem., 2023, 14, 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp(NMe)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol-water distribution coefficient (log D). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the in vivo performance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the in vitro characteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred.
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Affiliation(s)
- Neil Gerard Quigley
- Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany
| | | | - Beatrice Stefanie Ludwig
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany
| | - Frauke Richter
- Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany
| | - Nghia Trong Nguyen
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany
| | - Falco Reissig
- TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany
| | - Jakub Šimeček
- TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany
| | - Susanne Kossatz
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research, (TranslaTUM), School of Medicine and Health, Technische Universität München Munich Germany
| | - Johannes Notni
- Institute of Pathology, School of Medicine and Health, Technische Universität München Munich Germany
- TRIMT GmbH Carl-Eschebach-Str. 7 D-01454 Radeberg Germany
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Suwanchiwasiri K, Phanthaphol N, Somboonpatarakun C, Yuti P, Sujjitjoon J, Luangwattananun P, Maher J, Yenchitsomanus PT, Junking M. Bispecific T cell engager-armed T cells targeting integrin ανβ6 exhibit enhanced T cell redirection and antitumor activity in cholangiocarcinoma. Biomed Pharmacother 2024; 175:116718. [PMID: 38744221 DOI: 10.1016/j.biopha.2024.116718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/25/2024] [Accepted: 05/06/2024] [Indexed: 05/16/2024] Open
Abstract
Advanced cholangiocarcinoma (CCA) presents a clinical challenge due to limited treatment options, necessitating exploration of innovative therapeutic approaches. Bispecific T cell engager (BTE)-armed T cell therapy shows promise in hematological and solid malignancies, offering potential advantages in safety over continuous BTE infusion. In this context, we developed a novel BTE, targeting CD3 on T cells and integrin αvβ6, an antigen elevated in various epithelial malignancies, on cancer cells. The novel BTE was generated by fusing an integrin αvβ6-binding peptide (A20) to an anti-CD3 (OKT3) single-chain variable fragment (scFv) through a G4S peptide linker (A20/αCD3 BTE). T cells were then armed with A20/αCD3 BTE (A20/αCD3-armed T cells) and assessed for antitumor activity. Our results highlight the specific binding of A20/αCD3 BTE to CD3 on T cells and integrin αvβ6 on target cells, effectively redirecting T cells towards these targets. After co-culture, A20/αCD3-armed T cells exhibited significantly heightened cytotoxicity against integrin αvβ6-expressing target cells compared to unarmed T cells in both KKU-213A cells and A375.β6 cells. Moreover, in a five-day co-culture, A20/αCD3-armed T cells demonstrated superior cytotoxicity against KKU-213A spheroids compared to unarmed T cells. Importantly, A20/αCD3-armed T cells exhibited an increased proportion of the effector memory T cell (Tem) subset, upregulation of T cell activation markers, enhanced T cell proliferation, and increased cytolytic molecule/cytokine production, when compared to unarmed T cells in an integrin αvβ6-dependent manner. These findings support the potential of A20/αCD3-armed T cells as a novel therapeutic approach for integrin αvβ6-expressing cancers.
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Affiliation(s)
- Kwanpirom Suwanchiwasiri
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand; Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nattaporn Phanthaphol
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; School of Cardiovascular and Medical Health, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
| | - Chalermchai Somboonpatarakun
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pornpimon Yuti
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jatuporn Sujjitjoon
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Piriya Luangwattananun
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - John Maher
- King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, Guy's Cancer Centre, Great Maze Pond, London, United Kingdom
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Mutita Junking
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Molnar O, Straciuc OM, Mihuțiu S, Lazăr L. Impact of PET/CT Imaging with FDG in Locally Advanced Cervical Carcinoma-A Literature Review. Curr Oncol 2024; 31:2508-2526. [PMID: 38785469 PMCID: PMC11119194 DOI: 10.3390/curroncol31050188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/27/2024] [Accepted: 04/28/2024] [Indexed: 05/25/2024] Open
Abstract
Positron emission tomography (PET) and computed tomography (CT) have evolved as a pivotal diagnostic modality in the field of oncology. With its increasing application in staging and ready availability, it becomes imperative for committed radiation oncologists to possess a complete analysis and understanding of integration of molecular imaging, which can be helpful for radiation planning, while also acknowledging its possible limitations and challenges. A significant obstacle lies in the synthesis and design of tumor-specific bmolecules for diagnosing and treating cancer. The utilization of radiation in medical biochemistry and biotechnology, encompassing diagnosis, therapy, and control of biological systems, is encapsulated under the umbrella term "nuclear medicine". Notably, the application of various radioisotopes in pharmaceutics has garnered significant attention, particularly in the realm of delivery systems for drugs, DNA, and imaging agents. The present article provides a comprehensive review of use of novel techniques PET and CT with major positron-emitting radiopharmaceuticals currently in progress or utilized in clinical practice with their integration into imaging and radiation therapy.
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Affiliation(s)
- Ottó Molnar
- Doctoral Studies Department, Biomedical Science, 410087 Oradea, Romania
| | - Oreste Mihai Straciuc
- Doctoral Studies Department, Biomedical Science, 410087 Oradea, Romania
- Centrul PET/CT Pozitron Diagnosztika, 410035 Oradea, Romania
| | - Simona Mihuțiu
- Department of Medicine-Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, 410073 Oradea, Romania
- Oncology Department, Pelican Hospital, 410469 Oradea, Romania
| | - Liviu Lazăr
- Doctoral Studies Department, Biomedical Science, 410087 Oradea, Romania
- Department of Medicine-Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, 410073 Oradea, Romania
- Băile Felix Medical Rehabilitation Hospital, 417500 Băile Felix, Romania
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Lyon RP, Jonas M, Frantz C, Trueblood ES, Yumul R, Westendorf L, Hale CJ, Stilwell JL, Yeddula N, Snead KM, Kumar V, Patilea-Vrana GI, Klussman K, Ryan MC. SGN-B6A: A New Vedotin Antibody-Drug Conjugate Directed to Integrin Beta-6 for Multiple Carcinoma Indications. Mol Cancer Ther 2023; 22:1444-1453. [PMID: 37619980 PMCID: PMC10690100 DOI: 10.1158/1535-7163.mct-22-0817] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 06/30/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023]
Abstract
Integrin beta-6, a component of the heterodimeric adhesion receptor alpha-v/beta-6, is overexpressed in numerous solid tumors. Its expression has been shown by multiple investigators to be a negative prognostic indicator in diverse cancers including colorectal, non-small cell lung, gastric, and cervical. We developed SGN-B6A as an antibody-drug conjugate (ADC) directed to integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE) to cancer cells. The antibody component of SGN-B6A is specific for integrin beta-6 and does not bind other alpha-v family members. In preclinical studies, this ADC has demonstrated activity in vivo in models derived from non-small cell lung, pancreatic, pharyngeal, and bladder carcinomas spanning a range of antigen expression levels. In nonclinical toxicology studies in cynomolgus monkeys, doses of up to 5 mg/kg weekly for four doses or 6 mg/kg every 3 weeks for two doses were tolerated. Hematologic toxicities typical of MMAE ADCs were dose limiting, and no significant target-mediated toxicity was observed. A phase I first-in-human study is in progress to evaluate the safety and antitumor activity of SGN-B6A in a variety of solid tumors known to express integrin beta-6 (NCT04389632).
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11
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Liu F, Wu Q, Dong Z, Liu K. Integrins in cancer: Emerging mechanisms and therapeutic opportunities. Pharmacol Ther 2023:108458. [PMID: 37245545 DOI: 10.1016/j.pharmthera.2023.108458] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/10/2023] [Accepted: 05/22/2023] [Indexed: 05/30/2023]
Abstract
Integrins are vital surface adhesion receptors that mediate the interactions between the extracellular matrix (ECM) and cells and are essential for cell migration and the maintenance of tissue homeostasis. Aberrant integrin activation promotes initial tumor formation, growth, and metastasis. Recently, many lines of evidence have indicated that integrins are highly expressed in numerous cancer types and have documented many functions of integrins in tumorigenesis. Thus, integrins have emerged as attractive targets for the development of cancer therapeutics. In this review, we discuss the underlying molecular mechanisms by which integrins contribute to most of the hallmarks of cancer. We focus on recent progress on integrin regulators, binding proteins, and downstream effectors. We highlight the role of integrins in the regulation of tumor metastasis, immune evasion, metabolic reprogramming, and other hallmarks of cancer. In addition, integrin-targeted immunotherapy and other integrin inhibitors that have been used in preclinical and clinical studies are summarized.
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Affiliation(s)
- Fangfang Liu
- Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| | - Qiong Wu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China; Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Zigang Dong
- Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China; Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Tianjian Advanced Biomedical Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Kangdong Liu
- Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China; Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan 450000, China; Tianjian Advanced Biomedical Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan 450000, China.
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12
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Benfante V, Stefano A, Ali M, Laudicella R, Arancio W, Cucchiara A, Caruso F, Cammarata FP, Coronnello C, Russo G, Miele M, Vieni A, Tuttolomondo A, Yezzi A, Comelli A. An Overview of In Vitro Assays of 64Cu-, 68Ga-, 125I-, and 99mTc-Labelled Radiopharmaceuticals Using Radiometric Counters in the Era of Radiotheranostics. Diagnostics (Basel) 2023; 13:diagnostics13071210. [PMID: 37046428 PMCID: PMC10093267 DOI: 10.3390/diagnostics13071210] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023] Open
Abstract
Radionuclides are unstable isotopes that mainly emit alpha (α), beta (β) or gamma (γ) radiation through radiation decay. Therefore, they are used in the biomedical field to label biomolecules or drugs for diagnostic imaging applications, such as positron emission tomography (PET) and/or single-photon emission computed tomography (SPECT). A growing field of research is the development of new radiopharmaceuticals for use in cancer treatments. Preclinical studies are the gold standard for translational research. Specifically, in vitro radiopharmaceutical studies are based on the use of radiopharmaceuticals directly on cells. To date, radiometric β- and γ-counters are the only tools able to assess a preclinical in vitro assay with the aim of estimating uptake, retention, and release parameters, including time- and dose-dependent cytotoxicity and kinetic parameters. This review has been designed for researchers, such as biologists and biotechnologists, who would like to approach the radiobiology field and conduct in vitro assays for cellular radioactivity evaluations using radiometric counters. To demonstrate the importance of in vitro radiopharmaceutical assays using radiometric counters with a view to radiogenomics, many studies based on 64Cu-, 68Ga-, 125I-, and 99mTc-labeled radiopharmaceuticals have been revised and summarized in this manuscript.
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Affiliation(s)
- Viviana Benfante
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Alessandro Stefano
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Muhammad Ali
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
| | | | - Walter Arancio
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
| | - Antonino Cucchiara
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Fabio Caruso
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Francesco Paolo Cammarata
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Claudia Coronnello
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
| | - Giorgio Russo
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
| | - Monica Miele
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
| | - Alessandra Vieni
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
| | - Anthony Yezzi
- Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Albert Comelli
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
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13
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Fan D, Zhang C, Luo Q, Li B, Ai L, Li D, Jia W. In vivo evaluation of integrin αvβ6-targeting peptide in NSCLC and brain metastasis. Front Oncol 2023; 13:1070967. [PMID: 36968997 PMCID: PMC10036820 DOI: 10.3389/fonc.2023.1070967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/23/2023] [Indexed: 03/12/2023] Open
Abstract
IntroductionIntegrin αvβ6, which is upregulated in malignancies and remains absent or weak in normal tissue, is a promising target in molecular imaging therapeutics. In vivo imaging of integrin αvβ6 could therefore be valuable for early tumor detection and intraoperative guidance.MethodsIn this study, integrin αvβ6-targeting probe G2-SFLAP3 was labeled with near-infrared (NIR) dye Cy5.5 or radioisotope 68Ga. The resulting probes were evaluated in integrin αvβ6-positive A549 and αvβ6-negative H1703 xenograft mice models.ResultsThe cellar uptake of G2-SFLAP3-Cy5.5 was consistent with the expression of integrin αvβ6. Both subcutaneous and brain metastatic A549 tumors could be clearly visualized by NIR fluorescent imaging of G2-SFLAP3-Cy5.5. A549 tumors demonstrated the highest G2-SFLAP3-Cy5.5 accumulation at 4h post-injection (p.i.) and remain detectable at 84h p.i. The fluorescent signal of G2-SFLAP3-Cy5.5 was significantly reduced in H1703 and A549-blocking groups. Consistently, small-animal PET imaging showed tumor-specific accumulation of 68Ga-DOTA-G2-SFLAP3.DiscussionG2-SFLAP3 represents a promising agent for noninvasive imaging of non-small cell lung cancer (NSCLC) and brain metastases.
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Affiliation(s)
- Di Fan
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chengkai Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qi Luo
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China
| | - Baowang Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lin Ai
- Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Lin Ai, ; Deling Li, ; Wang Jia,
| | - Deling Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Lin Ai, ; Deling Li, ; Wang Jia,
| | - Wang Jia
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Lin Ai, ; Deling Li, ; Wang Jia,
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Matsumoto Y, Kage H, Morota M, Zokumasu K, Ando T, Maemura K, Watanabe K, Kawakami M, Hinata M, Ushiku T, Nakajima J, Nagase T. Integrin alpha 2 is associated with tumor progression and postoperative recurrence in non-small cell lung cancer. Jpn J Clin Oncol 2023; 53:63-73. [PMID: 36151049 DOI: 10.1093/jjco/hyac148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 08/29/2022] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Integrins are transmembrane proteins that mediate cell adhesion to extracellular matrix. Whereas expression of integrin alpha 2 is associated with motility, invasiveness and cellular differentiation in various tumors, the role of integrin alpha 2 in lung cancer has not been studied in detail. The aim of this study was to determine whether and how aberrant integrin alpha 2 expression in non-small cell lung cancer leads to different outcomes. METHODS We measured expression of integrin alpha 2 by quantitative polymerase chain reaction in 100 samples collected from non-small cell lung cancer patients who had undergone surgical resection. We assigned patients to high and low expression groups and analyzed survival. Cellular morphology, adhesion, proliferation, migration and invasion were examined in human lung cancer cell lines. RESULTS Among 100 cases, 41 were female, with a median age of 71 years. High expression of integrin alpha 2 in non-small cell lung cancer was associated with lower recurrence-free survival (P = 0.004). Overexpression of integrin alpha 2 in cell lines had no effect on cell proliferation or invasion but resulted in increased cell size (1416 μm2 versus 470 μm2 in H522 cells, P < 0.001; 1822 μm2 versus 1029 μm2 in H661 cells, P = 0.02), adhesion (P < 0.001 in H522 and H661 cells) and migration (gap area filled was 71% versus 36% in H522 cells, P < 0.001; 57% versus 26% in H661 cells, P = 0.001). These changes were suppressed by E7820, an inhibitor of integrin alpha 2. CONCLUSIONS Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence.
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Affiliation(s)
- Yoko Matsumoto
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Hidenori Kage
- Next-Generation Precision Medicine Development Laboratory, The University of Tokyo, Tokyo, Japan
| | - Mizuki Morota
- Department of Thoracic Surgery, The University of Tokyo, Tokyo, Japan
| | - Koichi Zokumasu
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Ando
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Keita Maemura
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Kousuke Watanabe
- Department of Clinical Laboratory, The University of Tokyo, Tokyo, Japan
| | - Masanori Kawakami
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Jun Nakajima
- Department of Thoracic Surgery, The University of Tokyo, Tokyo, Japan
| | - Takahide Nagase
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
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15
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Aleman J, Young CD, Karam SD, Wang XJ. Revisiting laminin and extracellular matrix remodeling in metastatic squamous cell carcinoma: What have we learned after more than four decades of research? Mol Carcinog 2023; 62:5-23. [PMID: 35596706 PMCID: PMC9676410 DOI: 10.1002/mc.23417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023]
Abstract
Patients with squamous cell carcinoma (SCC) have significantly lower survival upon the development of distant metastases. The extracellular matrix (ECM) is a consistent yet dynamic influence on the metastatic capacity of SCCs. The ECM encompasses a milieu of structural proteins, signaling molecules, and enzymes. Just over 40 years ago, the fibrous ECM glycoprotein laminin was identified. Roughly four decades of research have revealed a pivotal role of laminins in metastasis. However, trends in ECM alterations in some cancers have been applied broadly to all metastatic diseases, despite evidence that these characteristics vary by tumor type. We will summarize how laminins influence the SCC metastatic process exclusively. Enhanced laminin protein deposition occurs at the invasive edge of SCC tumors, which correlates with elevated levels of laminin-binding β1 integrins on SCC cells, increased MMP-3 presence, worse prognosis, and lymphatic dissemination. Although these findings are significant, gaps in knowledge of the formation of a premetastatic niche, the processes of intra- and extravasation, and the contributions of the ECM to SCC metastatic cell dormancy persist. Bridging these gaps requires novel in vitro systems and animal models that reproduce tumor-stromal interactions and spontaneous metastasis seen in the clinic. These advances will allow accurate assessment of laminins to predict responders to transforming growth factor-β inhibitors and immunotherapy, as well as potential combinatorial therapies with the standard of care. Such clinical interventions may drastically improve quality of life and patient survival by explicitly targeting SCC metastasis.
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Affiliation(s)
- John Aleman
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christian D. Young
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Sana D. Karam
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Xiao-Jing Wang
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, Colorado, USA
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16
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Nakamoto R, Ferri V, Duan H, Hatami N, Goel M, Rosenberg J, Kimura R, Wardak M, Haywood T, Kellow R, Shen B, Park W, Iagaru A, Gambhir SS. Pilot-phase PET/CT study targeting integrin α vβ 6 in pancreatic cancer patients using the cystine-knot peptide-based 18F-FP-R 01-MG-F2. Eur J Nucl Med Mol Imaging 2022; 50:184-193. [PMID: 34729628 DOI: 10.1007/s00259-021-05595-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/13/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE A novel cystine-knot peptide-based PET radiopharmaceutical, 18F-FP-R01-MG-F2 (knottin), was developed to selectively bind to human integrin αvβ6 which is overexpressed in pancreatic cancer. The purpose of this study is to evaluate the safety, biodistribution, dosimetry, and lesion uptake of 18F-FP-R01-MG-F2 in patients with pancreatic cancer. METHODS Fifteen patients (6 men, 9 women) with histologically confirmed pancreatic cancer were prospectively enrolled and underwent knottin PET/CT between March 2017 and February 2021 (ClinicalTrials.gov Identifier NCT02683824). Vital signs and laboratory results were collected before and after the imaging scans. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 24 normal tissues and pancreatic cancer lesions for each patient. From the biodistribution data, the organ doses and whole-body effective dose were calculated using OLINDA/EXM software. RESULTS There were no significant changes in vital signs or laboratory values that qualified as adverse events or serious adverse events. At 1 h post-injection, areas of high 18F-FP-R01-MG-F2 uptake included the pituitary gland, stomach, duodenum, kidneys, and bladder (average SUVmean: 9.7-14.5). Intermediate uptake was found in the normal pancreas (average SUVmean: 4.5). Mild uptake was found in the lungs and liver (average SUVmean < 1.0). The effective dose was calculated to be 2.538 × 10-2 mSv/MBq. Knottin PET/CT detected all known pancreatic tumors in the 15 patients, although it did not detect small peri-pancreatic lymph nodes of less than 1 cm in short diameter in two of three patients who had lymph node metastases at surgery. Knottin PET/CT detected distant metastases in the lungs (n = 5), liver (n = 4), and peritoneum (n = 2), confirmed by biopsy and/or contrast-enhanced CT. CONCLUSION 18F-FP-R01-MG-F2 is a safe PET radiopharmaceutical with an effective dose comparable to other diagnostic agents. Evaluation of the primary pancreatic cancer and distant metastases with 18F-FP-R01-MG-F2 PET is feasible, but larger studies are required to define the role of this approach. TRIAL REGISTRATION NCT02683824.
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Affiliation(s)
- Ryusuke Nakamoto
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Valentina Ferri
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Heying Duan
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Negin Hatami
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Mahima Goel
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Jarrett Rosenberg
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
| | - Richard Kimura
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Mirwais Wardak
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Tom Haywood
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Rowaid Kellow
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Bin Shen
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Walter Park
- Division of Gastroenterology and Hepatology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
| | - Andrei Iagaru
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA.
| | - Sanjiv Sam Gambhir
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, 300 Pasteur Drive, H2200, Stanford, CA, 94305-5281, USA
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5281, USA
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Corti A, Anderluzzi G, Curnis F. Neuropilin-1 and Integrins as Receptors for Chromogranin A-Derived Peptides. Pharmaceutics 2022; 14:2555. [PMID: 36559048 PMCID: PMC9785887 DOI: 10.3390/pharmaceutics14122555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Human chromogranin A (CgA), a 439 residue-long member of the "granin" secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the many biological activities observed in experimental and preclinical models for CgA and its most investigated fragments (vasostatin-I and catestatin), limited information is available on the receptor mechanisms underlying these effects. The interaction of vasostatin-1 with membrane phospholipids and the binding of catestatin to nicotinic and b2-adrenergic receptors have been proposed as important mechanisms for some of their effects on the cardiovascular and sympathoadrenal systems. Recent studies have shown that neuropilin-1 and certain integrins may also work as high-affinity receptors for CgA, vasostatin-1 and other fragments. In this case, we review the results of these studies and discuss the structural requirements for the interactions of CgA-related peptides with neuropilin-1 and integrins, their biological effects, their mechanisms, and the potential exploitation of compounds that target these ligand-receptor systems for cancer diagnosis and therapy. The results obtained so far suggest that integrins (particularly the integrin avb6) and neuropilin-1 are important receptors that mediate relevant pathophysiological functions of CgA and CgA fragments in angiogenesis, wound healing, and tumor growth, and that these interactions may represent important targets for cancer imaging and therapy.
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Affiliation(s)
- Angelo Corti
- Faculty of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Giulia Anderluzzi
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Flavio Curnis
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment. Int J Mol Sci 2022; 23:ijms232012346. [PMID: 36293202 PMCID: PMC9603893 DOI: 10.3390/ijms232012346] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/20/2022] Open
Abstract
Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis. This review focuses on an arginine-glycine-aspartic acid (RGD)-dependent integrin αVβ6, its biology, and its role in healthy humans. We examine the implications of αVβ6 in cancer progression and the promotion of epithelial-mesenchymal transition (EMT) by contributing to the activation of transforming growth factor beta TGF-β. Although αvβ6 is crucial for proper function in healthy people, it has also been validated as a target for cancer treatment. This review briefly considers aspects of targeting αVβ6 in the clinic via different therapeutic modalities.
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HPV-Induced MiR-21 Promotes Epithelial Mesenchymal Transformation and Tumor Progression in Cervical Cancer Cells through the TGFβ R2/hTERC Pathway. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:6297694. [PMID: 36105448 PMCID: PMC9458404 DOI: 10.1155/2022/6297694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022]
Abstract
Cervical cancer (CC) is a common malignant tumor in women. It ranks first among the malignant tumors of woman reproductive organs and is one of the most important cancers in the world. Current studies suggest that human papillomavirus (HPV) infection, especially high-risk persistent infection, is the basic cause of cervical precancerous lesions and cervical cancer. MicroRNA-21 (miR-21) plays a role similar to oncogenes in the occurrence and growth of malignant tumors and can be developed as a potential target for treating malignant tumors. Recently, the study of the mechanism of malignant invasion and metastasis has made great progress. The current consensus is that the invasion and metastasis of malignant tumors is a complicated biological process with multistep and multigene control; the process of epithelial mesenchymal transition (EMT) may be the initial event of invasion and metastasis of epithelial malignant tumors. EMT means that epithelial cells obtain the characteristics of mesenchymal cells, which has main characteristics such as the loss of epithelial cell characteristics and the achievement of mesenchymal cell features, and then induce epithelial cells to acquire the ability of migration and invasion, and participate in many physiological and pathological processes of human body, including embryogenesis, organ differentiation, tissue inflammation, and wound healing. Research has proved that miR-21 is associated with the invasion and metastasis of cervical cancer, and its specific mechanism has not been completely clear; EMT exerts a significant effect on the invasion and metastasis of epithelial malignant tumors; we speculate whether miR-21 regulates the EMT process of cervical cancer cells. ELISA and RT-PCR studied HPV-induced cervical cancer cells, and it was found that HPV may induce miR-21 to pass through the TGF β R2/hTERC pathway which promotes epithelial stromal transformation and tumor progression of cervical cancer cells.
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20
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Hung KY, Kowalczyk R, Desai A, Brimble MA, Marshall JF, Harris PWR. Synthesis and Systematic Study on the Effect of Different PEG Units on Stability of PEGylated, Integrin-αvβ6-Specific A20FMDV2 Analogues in Rat Serum and Human Plasma. Molecules 2022; 27:4331. [PMID: 35889207 PMCID: PMC9316855 DOI: 10.3390/molecules27144331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in blood caused by rapid renal excretion and its reported high susceptibility to serum proteases. The incorporation of poly (ethylene glycol) chains, coined PEGylation, is a well-established approach to improve the pharmacokinetic properties of drug molecules. Here, we report a systematic study on the incorporation of a varying number of ethylene glycol units (1-20) into the A20FMDV2 peptide to establish the effects of PEGylation size on the peptide stability in both rat serum and human plasma. In addition, the effect of acetyl and propionyl PEGylation handles on peptide stability is also described. Selected peptide analogues were assessed for integrin-αvβ6-targeted binding, showing good specificity and activity in vitro. Stability studies in rat serum established that all of the PEGylated peptides displayed good stability, and an A20FMDV2 peptide containing twenty ethylene glycol units (PEG20) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG2 and PEG5) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6.
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Affiliation(s)
- Kuo-yuan Hung
- The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand; (K.-y.H.); (M.A.B.)
| | - Renata Kowalczyk
- The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand; (K.-y.H.); (M.A.B.)
| | - Ami Desai
- Centre for Tumour Biology, Barts Cancer Institute-Cancer Research UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK;
| | - Margaret A. Brimble
- The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand; (K.-y.H.); (M.A.B.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
- The School of Biological Sciences, University of Auckland, 3A Symonds St, Auckland 1010, New Zealand
| | - John F. Marshall
- Centre for Tumour Biology, Barts Cancer Institute-Cancer Research UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK;
| | - Paul W. R. Harris
- The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand; (K.-y.H.); (M.A.B.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
- The School of Biological Sciences, University of Auckland, 3A Symonds St, Auckland 1010, New Zealand
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21
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Marvin DL, Spaans VM, de Kroon CD, Slieker RC, Khelil M, Ten Dijke P, Ritsma L, Jordanova ES. Low Transforming Growth Factor-β Pathway Activity in Cervical Adenocarcinomas. Front Oncol 2022; 12:797453. [PMID: 35756604 PMCID: PMC9213724 DOI: 10.3389/fonc.2022.797453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 05/12/2022] [Indexed: 12/24/2022] Open
Abstract
Cervical cancer is the fourth most common cancer in women worldwide. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the most common histological types, with AC patients having worse prognosis. Over the last two decades, incidence rates of AC have increased, highlighting the importance of further understanding AC tumorigenesis, and the need to investigate new treatment options. The cytokine TGF-β functions as a tumour suppressor in healthy tissue. However, in tumour cells this suppressive function can be overcome. Therefore there is an increasing interest in using TGF-β inhibitors in the treatment of cancer. Here, we hypothesize that TGF-β plays a different role in SCC and AC. Analysis of RNA-seq data from the TCGA, using a TGF-β response signature, resulted in separate clustering of the two subtypes. We further investigated the expression of TGF-β-signalling related proteins (TβR1/2, SMAD4, pSMAD2, PAI-1, αvβ6 and MMP2/9) in a cohort of 62 AC patients. Low TβR2 and SMAD4 expression was associated with worse survival in AC patients and interestingly, high PAI-1 and αvβ6 expression was also correlated with worse survival. Similar correlations of TβR2, PAI-1 and αvβ6 with clinical parameters were found in previously reported SCC analyses. However, when comparing expression levels between SCC and AC patient samples, pSMAD2, SMAD4, PAI-1 and αvβ6 showed lower expression in AC compared to SCC. Because of the low expression of core TβR1/2, (p-)SMAD2 and SMAD4 proteins and the correlation with worse prognosis, TGF-β pathway most likely leads to tumour inhibitory effects in AC and therefore the use of TGF-β inhibitors would not be recommended. However, given the correlation of PAI-1 and αvβ6 with poor prognosis, the use of TGF- β inhibitors might be of interest in SCC and in the subsets of AC patients with high expression of these TGF-β associated proteins.
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Affiliation(s)
- Dieuwke L Marvin
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Vivian M Spaans
- Department of Gynaecology and Obstetrics, Leiden University Medical Center, Leiden, Netherlands.,Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - Cor D de Kroon
- Department of Gynaecology and Obstetrics, Leiden University Medical Center, Leiden, Netherlands
| | - Roderick C Slieker
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.,Department of Epidemiology and Data Science, Amsterdam University Medical Center (UMC), location VU University Medical Center (VUmc), Amsterdam, Netherlands
| | - Maryam Khelil
- Department of Gynaecology and Obstetrics, Center Gynaecological Oncology Amsterdam, Amsterdam University Medical Center (UMC), location VU University Medical Center (VUmc), Amsterdam, Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Laila Ritsma
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Ekaterina S Jordanova
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.,Department of Gynaecology and Obstetrics, Center Gynaecological Oncology Amsterdam, Amsterdam University Medical Center (UMC), location VU University Medical Center (VUmc), Amsterdam, Netherlands.,Department of Urology, The Netherlands Cancer Institute, Amsterdam, Netherlands
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22
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Nguyen BA, Ho J, De La Cruz Diaz JS, Nishimura S, Kaplan DH. TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma. J Dermatol Sci 2022; 106:2-11. [PMID: 35277328 PMCID: PMC9124681 DOI: 10.1016/j.jdermsci.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/12/2022] [Accepted: 01/26/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Integrins avβ6 and avβ8 are expressed by keratinocytes and transactivate latent TGFβ. In a murine model, integrin mediated activation of TGFβ has been shown to be critical in maintaining skin homeostasis, specifically playing roles in epidermal retention of Langerhans cells and resident memory cells T cells (Trm). OBJECTIVE We examine expression of Integrins β6 and β8 in human skin, inflammatory skin disease, benign nevi, and melanoma and hypothesize that integrin expression is dysregulated in disease. METHODS Using immunohistochemistry, we stained tissue from normal human skin (n = 8), psoriasis (n = 6), atopic dermatitis (n = 6), lichen planus (n = 5), benign nevi (n = 24), and melanoma (n = 25) with anti-integrin β6 and anti-integrin β8 to survey expression pattern. We also performed a retrospective chart review in the melanoma cohort to examine if integrin β6 and β8 expression was associated with increased Breslow depth and worse prognostic staging. RESULTS Here, we show that human keratinocytes express integrins β6 and β8, similar to murine keratinocytes. We also found that inflammatory skin conditions have increased Integrin β6, but not Integrin β8 expression. Furthermore, we identified that melanomas have greatly increased expression of integrin β8 compared to nevi. Additionally, high expression of integrin β8 was correlated with greater Breslow depth at diagnosis and with worse prognostic staging. CONCLUSION These findings demonstrate that like murine keratinocytes, human keratinocytes express integrin β6 and β8 under steady state conditions. Moreover, altered integrin expression may participate in the development or maintenance of cutaneous inflammation as well as tumor immune evasion.
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Affiliation(s)
- Breanna A Nguyen
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jonhan Ho
- Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jacinto S De La Cruz Diaz
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Stephen Nishimura
- Department of Pathology, University of California San Francisco, San Francisco, CA, United States
| | - Daniel H Kaplan
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, United States.
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23
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Huynh TT, Sreekumar S, Mpoy C, Rogers BE. A comparison of 64Cu-labeled bi-terminally PEGylated A20FMDV2 peptides targeting integrin α νβ 6. Oncotarget 2022; 13:360-372. [PMID: 35186193 PMCID: PMC8849274 DOI: 10.18632/oncotarget.28197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/07/2022] [Indexed: 11/25/2022] Open
Abstract
Expression of epithelial-specific integrin ανβ6 is up-regulated in various aggressive cancers and serves as a prognostic marker. Integrin-targeted PET imaging probes have been successfully developed and tested in the clinic. Radiotracers based on the peptide A20FMDV2 derived from foot-and-mouth disease virus represent specific and selective PET ligands for imaging ανβ6-positive cancers. The present study aims to describe the radiolabeling, in vitro and in vivo evaluation of a bi-terminally PEGylated A20FMDV2 conjugated with DOTA or PCTA for 64Cu radiolabeling. Stability studies showed radiolabeled complexes remained stable up to 24 h in PBS and human serum. In vitro cell assays in CaSki cervical cancer cells and BxPC-3 pancreatic cancer cells confirmed that the peptides displayed high affinity for αvβ6 with Kd values of ~50 nM. Biodistribution studies revealed that [64Cu] Cu-PCTA-(PEG28)2-A20FMDV2 exhibited higher tumor uptake (1.63 ± 0.53 %ID/g in CaSki and 3.86 ± 0.58 %ID/g in BxPC-3 at 1 h) when compared to [64Cu]Cu-DOTA-(PEG28)2-A20FMDV2 (0.95 ± 0.29 %ID/g in CaSki and 2.12 ± 0.83 %ID/g in BxPC-3 at 1 h) . However, higher tumor uptake was accompanied by increased radioactive uptake in normal organs. Therefore, both peptides are appropriate for imaging ανβ6-positive lesions although further optimization is needed to improve tumor-to-normal-tissue ratios.
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Affiliation(s)
- Truc T Huynh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.,Department of Chemistry, Washington University, St. Louis, MO, USA
| | - Sreeja Sreekumar
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Cedric Mpoy
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Buck E Rogers
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
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24
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Huynh TT, Sreekumar S, Mpoy C, Rogers BE. Therapeutic Efficacy of 177Lu-Labeled A20FMDV2 Peptides Targeting ανβ6. Pharmaceuticals (Basel) 2022; 15:ph15020229. [PMID: 35215341 PMCID: PMC8876964 DOI: 10.3390/ph15020229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 12/27/2022] Open
Abstract
Integrin ανβ6 promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting ανβ6 with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for ανβ6. However, one concern of these ανβ6 integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either 68Ga for imaging or 177Lu for therapy. PET imaging with [68Ga]Ga-DOTA-(PEG28)2-A20FMDV2 revealed specific tumor uptake in ανβ6-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)2-A20FMDV2 and IBA-DOTA-(PEG28)2-A20FMDV2 were radiolabeled with 177Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both 177Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an ανβ6-positive tumor.
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Affiliation(s)
- Truc Thao Huynh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Sreeja Sreekumar
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
| | - Cedric Mpoy
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
| | - Buck Edward Rogers
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
- Correspondence:
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25
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Busenhart P, Montalban-Arques A, Katkeviciute E, Morsy Y, Van Passen C, Hering L, Atrott K, Lang S, Garzon JFG, Naschberger E, Hartmann A, Rogler G, Stürzl M, Spalinger MR, Scharl M. Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer. J Immunother Cancer 2022; 10:jitc-2021-003465. [PMID: 35131862 PMCID: PMC8823245 DOI: 10.1136/jitc-2021-003465] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2021] [Indexed: 12/13/2022] Open
Abstract
Background Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer. Methods Using orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD). Results We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy. Conclusions These findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy.
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Affiliation(s)
- Philipp Busenhart
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ana Montalban-Arques
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Egle Katkeviciute
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Yasser Morsy
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Chiara Van Passen
- Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Marianne Rebecca Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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26
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PET imaging of pancreatic cancer. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00207-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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27
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Pankova V, Thway K, Jones RL, Huang PH. The Extracellular Matrix in Soft Tissue Sarcomas: Pathobiology and Cellular Signalling. Front Cell Dev Biol 2021; 9:763640. [PMID: 34957097 PMCID: PMC8696013 DOI: 10.3389/fcell.2021.763640] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/09/2021] [Indexed: 11/22/2022] Open
Abstract
Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.
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Affiliation(s)
- Valeriya Pankova
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton, United Kingdom
| | - Khin Thway
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton, United Kingdom
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Robin L. Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom
- Division of Clinical Studies, The Institute of Cancer Research, Sutton, United Kingdom
| | - Paul H. Huang
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton, United Kingdom
- *Correspondence: Paul H. Huang,
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28
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IFIT3 (interferon induced protein with tetratricopeptide repeats 3) modulates STAT1 expression in small extracellular vesicles. Biochem J 2021; 478:3905-3921. [PMID: 34622927 PMCID: PMC9121857 DOI: 10.1042/bcj20210580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/14/2022]
Abstract
We have previously shown that the αvβ6 integrin plays a key role in promoting prostate cancer (PrCa) and it can be transferred to recipient cells via small extracellular vesicles (sEVs). Furthermore, we have reported in a proteomic analysis that αvβ6 integrin down-regulation increases the expression of IFIT3 (interferon induced protein with tetratricopeptide repeats 3) in PrCa cells and their derived sEVs. IFIT3 is a protein well known for being an antiviral effector, but recently its role in cancer has also been elucidated. To study the relationship between IFIT3 and STAT1 (signal transducer and activator of transcription 1), an upstream regulator of IFIT3, in PrCa cells and their released sEVs, we used CRISPR/Cas9 techniques to down-regulate the expression of the β6 integrin subunit, IFIT3 or STAT1. Our results show that IFIT3 and STAT1 are highly expressed in PrCa cells devoid of the β6 integrin subunit. However, IFIT3 but not STAT1, is present in sEVs derived from PrCa cells lacking the β6 integrin subunit. We demonstrate that loss of IFIT3 generates sEVs enriched in STAT1 but reduces the levels of STAT1 in the cells. As expected, IFIT3 is not detectable in STAT1 negative cells or sEVs. We thus propose that the observed STAT1 enrichment in sEVs is a compensatory mechanism for the loss of IFIT3. Overall, these results provide new insights into the intrinsic role of IFIT3 as a regulator of STAT1 expression in sEVs and in intercellular communication in PrCa.
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29
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Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov 2021; 21:60-78. [PMID: 34535788 PMCID: PMC8446727 DOI: 10.1038/s41573-021-00284-4] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins. Integrins are key signalling molecules that are present on the surface of subsets of cells and are therefore good potential therapeutic targets. In this Review, Hatley and colleagues discuss the development of integrin inhibitors, particularly the challenges in developing inhibitors for integrins that contain an αv-subunit, and suggest how these challenges could be addressed.
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Affiliation(s)
| | | | | | - R G Jenkins
- National Heart and Lung Institute, Imperial College London, London, UK
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Dzobo K. Integrins Within the Tumor Microenvironment: Biological Functions, Importance for Molecular Targeting, and Cancer Therapeutics Innovation. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:417-430. [PMID: 34191612 DOI: 10.1089/omi.2021.0069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many cellular functions important for solid tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell attachment receptors. With recent studies emphasizing the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that considerable attention is being paid to integrins. Several integrin antagonists are under clinical trials, with many demonstrating promising activity in patients with different cancers. A deeper knowledge of the functions of integrins within the TME is still required and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This expert review offers the latest synthesis in terms of the current knowledge of integrins functions within the TME and as potential molecular targets for cancer therapeutics innovation.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Sachindra S, Hellberg T, Exner S, Prasad S, Beindorff N, Rogalla S, Kimura R, Gambhir SS, Wiedenmann B, Grötzinger C. SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model. Front Oncol 2021; 11:684713. [PMID: 34136410 PMCID: PMC8200818 DOI: 10.3389/fonc.2021.684713] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/10/2021] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide 177Lu for targeting of PDAC. METHODS The expression of integrin αvβ6 in PDAC cell lines BxPC-3 and Capan-2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC-3 and Capan-2 cell lines as well as the maximum number of binding sites in these cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan-2 xenograft tumor mouse model. RESULTS RT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC-3 and Capan-2 cells. A competition binding assay revealed high affinity of the tracer with IC50 values of 1.69 nM and 9.46 nM for BxPC-3 and Capan-2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan-2 xenograft tumors (3.13 ± 0.63%IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors. CONCLUSION 177Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy.
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Affiliation(s)
- Sachindra Sachindra
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Teresa Hellberg
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Samantha Exner
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Sonal Prasad
- Berlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nicola Beindorff
- Berlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Stephan Rogalla
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Richard Kimura
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Sanjiv Sam Gambhir
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United States
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Molecular Cancer Research Center (MKFZ), Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
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Zheng X, Zhu Y, Wang X, Hou Y, Fang Y. Silencing of ITGB6 inhibits the progression of cervical carcinoma via regulating JAK/STAT3 signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:803. [PMID: 34268416 PMCID: PMC8246156 DOI: 10.21037/atm-21-1669] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/29/2021] [Indexed: 12/03/2022]
Abstract
Background Integrin β6 (ITGB6), a key submonomer of integrin αvβ6, plays an important role in epithelial-to-mesenchymal transition (EMT), wound healing, epithelial-derived tumor growth, fibrosis, and epithelial repair. However, the role of ITGB6 in cervical carcinoma (CC) remains elusive. Methods The expression levels of ITGB6 in CC tissues and cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony-forming, flow cytometry, and Transwell assay, respectively. The expression of related proteins, including EMT markers and the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling markers, were detected using western blotting. Results The ITGB6 expression in CC tissues and cells (C-33A, Hela, SiHa, and Caski) was remarkably higher than that in paracarcinoma tissues and ECT1/E6E7 cells. The data from The Cancer Genome Atlas (TCGA) data set suggested that patients with CC with high ITGB6 expression showed poorer overall survival (OS). Compared with the empty transfection group (si-NC), si-ITGB6 restrained the proliferation, migration, and invasion of SiHa and Hela cells, while promoting cell apoptosis. si-ITGB6 suppression decreased the expression of Snail, vimentin, and N-cadherin, while increasing E-cadherin expression. Further research showed that si-ITGB6 reduced p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 expression in the JAK/STAT3 signaling pathway. Interestingly, proliferation, migration, invasion, and the expressions of the molecular markers of the JAK/STAT3 signaling pathway and EMT pathway induced by ITGB6 were altered by RO8191 (JAK/STAT3 pathway activator). Furthermore, the protein expression levels of Snail, vimentin, N-cadherin, p-STAT3/STAT3, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues were higher than those in adjacent normal tissue, while the expression level of E-cadherin was downregulated in tumor tissues. Conclusions Silencing of ITGB6 restrains cell proliferation, migration and invasion, and promotes apoptosis in CC by inhibiting JAK/STAT signaling pathways. Thus, ITGB6 may perhaps be a new and useful candidate target for treating CC.
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Affiliation(s)
- Xiaoxia Zheng
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yanan Zhu
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Xiaoping Wang
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yanmei Hou
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
| | - Yingji Fang
- Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University/Jinan Maternity and Child Care Hospital Affiliated, Jinan, China
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Huang J, Zhang L, Wan D, Zhou L, Zheng S, Lin S, Qiao Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct Target Ther 2021; 6:153. [PMID: 33888679 PMCID: PMC8062524 DOI: 10.1038/s41392-021-00544-0] [Citation(s) in RCA: 424] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/17/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.
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Affiliation(s)
- Jiacheng Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Lele Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Dalong Wan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shengzhang Lin
- School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, China.
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China.
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China.
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Zhong C, Li ZX, Yang LJ, Wu G, Xiang B, Wang YL, Zhou Q. ITGB6 may promote proliferation and invasion in pancreatic cancer. Arch Med Sci 2021; 20:267-279. [PMID: 38414469 PMCID: PMC10895961 DOI: 10.5114/aoms/114039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/06/2019] [Indexed: 02/29/2024] Open
Abstract
Introduction The ITGB6 gene encoding a protein that can regulate the integrin αvβ6 heterodimer protein expression in different status was shown to play an important role in multiple human cancers, such as brain cancer, colon cancer and oral cancer, and is related to clinical progression. This study aims to explore the function and the mechanism of the ITGB6 gene or protein in pancreatic cancer. Material and methods We examined the expression of ITGB6 in pancreatic cancer using immunohistochemistry and analyzed the relationship between the expression of ITGB6 and the clinicopathologic features in pancreatic cancer patients. In addition, a bioinformatic method was used to analyze the ITGB6 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the correlation between high KIF23 expression and prognosis in pancreatic cancer patients. Moreover, colony formation assay, MTT assay, cell scratch, cell invasion and western blot assays in vitro and a xenograft mouse model in vivo were performed to analyze the effect of KIF23 on proliferation and invasion of pancreatic cancer cells. Results Increased expression of ITGB6 was significantly correlated with poor clinical outcome in both our clinical data and TCGA data of pancreatic cancer. Furthermore, functional assays revealed that ITGB6 knockdown in vivo and in vitro might inhibit cancer cell proliferation and the ability of invasion or migration. Conclusions Our data suggest that ITGB6 is associated with pancreatic cancer malignant progression. Hence, ITGB6 may serve as a potential target of pancreatic cancer for future research, and further study is needed.
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Affiliation(s)
- Chao Zhong
- Department of Traditional Chinese Medicine of Orthopedic and Traumatic, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Zhi-Xi Li
- Department of Respiratory Medicine, East Hospital, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Ling-Jing Yang
- Department of Respiratory Medicine, East Hospital, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Gang Wu
- Department of Hepatobiliary Surgery, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Bo Xiang
- Department of Cardiosurgery, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Yu-Lan Wang
- Department of Oncology, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
| | - Qing Zhou
- Department of Ultrasound, Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu City, Sichuan Province, China
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Desnoyers A, González C, Pérez-Segura P, Pandiella A, Amir E, Ocaña A. Integrin ανβ6 Protein Expression and Prognosis in Solid Tumors: A Meta-Analysis. Mol Diagn Ther 2021; 24:143-151. [PMID: 32100239 DOI: 10.1007/s40291-020-00450-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND OBJECTIVE Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ανβ6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ανβ6 integrin protein expression in solid tumors. METHODS A systematic search of electronic databases identified publications exploring the effect of ανβ6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ανβ6 integrins on OS. RESULTS Seventeen studies comprising 5795 patients met the inclusion criteria. High ανβ6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran's Q p < 0.001, I2 = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ανβ6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods. CONCLUSIONS High expression of ανβ6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ανβ6 integrin and its role as a therapeutic target are warranted.
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Affiliation(s)
- Alexandra Desnoyers
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada
| | - Carlos González
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada.,Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,CIC-Universidad de Salamanca, Salamanca, Spain.,Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (UCLM), Albacete, Spain
| | - Pedro Pérez-Segura
- Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Atanasio Pandiella
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,CIC-Universidad de Salamanca, Salamanca, Spain
| | - Eitan Amir
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, Toronto, ON, Canada
| | - Alberto Ocaña
- Experimental Therapeutics Unit, Medical Oncology Department, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain. .,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain. .,Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (UCLM), Albacete, Spain.
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Yang H, Kuo YH, Smith ZI, Spangler J. Targeting cancer metastasis with antibody therapeutics. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1698. [PMID: 33463090 DOI: 10.1002/wnan.1698] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022]
Abstract
Cancer metastasis, the spread of disease from a primary to a distal site through the circulatory or lymphatic systems, accounts for over 90% of all cancer related deaths. Despite significant progress in the field of cancer therapy in recent years, mortality rates remain dramatically higher for patients with metastatic disease versus those with local or regional disease. Although there is clearly an urgent need to develop drugs that inhibit cancer spread, the overwhelming majority of anticancer therapies that have been developed to date are designed to inhibit tumor growth but fail to address the key stages of the metastatic process: invasion, intravasation, circulation, extravasation, and colonization. There is growing interest in engineering targeted therapeutics, such as antibody drugs, that inhibit various steps in the metastatic cascade. We present an overview of antibody therapeutic approaches, both in the pipeline and in the clinic, that disrupt the essential mechanisms that underlie cancer metastasis. These therapies include classes of antibodies that indirectly target metastasis, including anti-integrin, anticadherin, and immune checkpoint blocking antibodies, as well as monoclonal and bispecific antibodies that are specifically designed to interrupt disease dissemination. Although few antimetastatic antibodies have achieved clinical success to date, there are many promising candidates in various stages of development, and novel targets and approaches are constantly emerging. Collectively, these efforts will enrich our understanding of the molecular drivers of metastasis, and the new strategies that arise promise to have a profound impact on the future of cancer therapeutic development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Huilin Yang
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Yun-Huai Kuo
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Zion I Smith
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jamie Spangler
- Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Bagati A, Kumar S, Jiang P, Pyrdol J, Zou AE, Godicelj A, Mathewson ND, Cartwright ANR, Cejas P, Brown M, Giobbie-Hurder A, Dillon D, Agudo J, Mittendorf EA, Liu XS, Wucherpfennig KW. Integrin αvβ6-TGFβ-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer. Cancer Cell 2021; 39:54-67.e9. [PMID: 33385331 PMCID: PMC7855651 DOI: 10.1016/j.ccell.2020.12.001] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 09/18/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.
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MESH Headings
- Animals
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/pharmacology
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Antineoplastic Agents, Immunological/therapeutic use
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Integrins/antagonists & inhibitors
- Integrins/genetics
- Integrins/metabolism
- Mice
- Neoplasm Transplantation
- SOXC Transcription Factors/genetics
- SOXC Transcription Factors/metabolism
- Sequence Analysis, RNA
- Signal Transduction/drug effects
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Cytotoxic/metabolism
- Transforming Growth Factor beta/genetics
- Triple Negative Breast Neoplasms/drug therapy
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/immunology
- Tumor Escape/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Archis Bagati
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA
| | - Sushil Kumar
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Peng Jiang
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Jason Pyrdol
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Angela E Zou
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Anze Godicelj
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Nathan D Mathewson
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Adam N R Cartwright
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Paloma Cejas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Anita Giobbie-Hurder
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Deborah Dillon
- Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA; Breast Oncology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - X Shirley Liu
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kai W Wucherpfennig
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Room 736, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA.
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38
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Cardle II, Jensen MC, Pun SH, Sellers DL. Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting. J Biol Chem 2021; 296:100657. [PMID: 33857478 PMCID: PMC8138772 DOI: 10.1016/j.jbc.2021.100657] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/03/2022] Open
Abstract
The integrin αvβ6 is an antigen expressed at low levels in healthy tissue but upregulated during tumorigenesis, which makes it a promising target for cancer imaging and therapy. A20FMDV2 is a 20-mer peptide derived from the foot-and-mouth disease virus that exhibits nanomolar and selective affinity for αvβ6 versus other integrins. Despite this selectivity, A20FMDV2 has had limited success in imaging and treating αvβ6+ tumors in vivo because of its poor serum stability. Here, we explore the cyclization and modification of the A20FMDV2 peptide to improve its serum stability without sacrificing its affinity and specificity for αvβ6. Using cysteine amino acid substitutions and cyclization by perfluoroarylation with decafluorobiphenyl, we synthesized six cyclized A20FMDV2 variants and discovered that two retained binding to αvβ6 with modestly improved serum stability. Further d-amino acid substitutions and C-terminal sequence optimization outside the cyclized region greatly prolonged peptide serum stability without reducing binding affinity. While the cyclized A20FMDV2 variants exhibited increased nonspecific integrin binding compared with the original peptide, additional modifications with the non-natural amino acids citrulline, hydroxyproline, and d-alanine were found to restore binding specificity, with some modifications leading to greater αvβ6 integrin selectivity than the original A20FMDV2 peptide. The peptide modifications detailed herein greatly improve the potential of utilizing A20FMDV2 to target αvβ6 in vivo, expanding opportunities for cancer targeting and therapy.
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Affiliation(s)
- Ian I Cardle
- Department of Bioengineering, University of Washington, Seattle, Washington, USA; Seattle Children's Therapeutics, Seattle, Washington, USA
| | - Michael C Jensen
- Department of Bioengineering, University of Washington, Seattle, Washington, USA; Seattle Children's Therapeutics, Seattle, Washington, USA; Department of Pediatrics, University of Washington, Seattle, Washington, USA; Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Suzie H Pun
- Department of Bioengineering, University of Washington, Seattle, Washington, USA
| | - Drew L Sellers
- Department of Bioengineering, University of Washington, Seattle, Washington, USA.
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Wu J, Cheng J, Zhang F, Luo X, Zhang Z, Chen S. Estrogen receptor α is involved in the regulation of ITGA8 methylation in estrogen receptor-positive breast cancer. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:993. [PMID: 32953793 PMCID: PMC7475494 DOI: 10.21037/atm-20-5220] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Integrin subunit α 8 (ITGA8) methylation has been associated with the development of several cancers, but its contribution to breast cancer remains unclear. The present study aimed to investigate the methylation status of ITGA8, and the underlying regulatory mechanisms of ITGA8 methylation in breast cancer. Methods ITGA8 expression was investigated using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database and the Breast Cancer Gene-Expression Miner v.4.4 (bc-GenExMiner v4.4). The association between ITGA8 expression levels and the survival rate of breast cancer patients was evaluated using The Cancer Genome Atlas (TCGA) database and Gene Expression-based Outcome for Breast Cancer Online (GOBO): Gene Set Analysis. Methylation-specific PCR (MSP) was used to detect the methylation of ITGA8. Protein level of ITGA8 was determined by Western blot analysis. Results ITGA8 was expressed at low levels in human breast cancer cells compared to non-tumorigenic breast cells and breast tissue, and was upregulated in estrogen receptor (ER)-positive tissue compared with ER-negative tissue (P<0.01). ITGA8 gene expression was negatively associated with breast tumor stage and survival rate in all breast cancer patients. However, ER-positive patients with low ITGA8 expression showed poorer distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) rates than patients with high ITGA8 expression. This was not observed in the ER-negative population. Mechanistically speaking, hypermethylation of ITGA8 was discovered in ER-positive breast cancer cells. Administration of the methylation inhibitor, 5-aza-2’-deoxycytidine (5-aza-dC), significantly elevated protein expression of ITGA8 in ER-positive breast cancer cells compared to ER-negative cells. The positive association between ITGA8 status and methylation was also observed in clinical tissue specimens. When treated with 17-beta-estradiol, an antagonist of ERα, 5-aza-dC-induced upregulation of ITGA8 in ER-positive breast cancer cells was no longer observed. Conclusions Low ITGA8 expression in ER-positive breast cancer might be caused by the hypermethylation of ITGA8, a process dependent on ERα. Our findings provide an important foundation for investigations into ITGA8-targeted treatment strategies for ER-positive breast cancer.
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Affiliation(s)
- Jingxun Wu
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jianghong Cheng
- Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Fuxing Zhang
- Department of General Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Xianyang Luo
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China.,Teaching Hospital of Fujian Medical University, Fuzhou, China
| | - Zhiming Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China.,Teaching Hospital of Fujian Medical University, Fuzhou, China
| | - Shuai Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China.,Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical Science, Xi'an Medical University, Xi'an, China.,Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.,Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China.,Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
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40
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Budhwani M, Lukowski SW, Porceddu SV, Frazer IH, Chandra J. Dysregulation of Stemness Pathways in HPV Mediated Cervical Malignant Transformation Identifies Potential Oncotherapy Targets. Front Cell Infect Microbiol 2020; 10:307. [PMID: 32670895 PMCID: PMC7330094 DOI: 10.3389/fcimb.2020.00307] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomically diverse regions, and the majority of cervical intraepithelial neoplasia and cancers arise within the cervical squamo-columnar junction where undifferentiated basal progenitor cells with stem cell properties are found. The cancer stem cell theory particularly associates tumorigenesis, invasion, dissemination, and metastasis with cancer cells exhibiting stem cell properties. In this perspective, we discuss evidence of a cervical cancer stem cell niche and explore the association of stemness related genes with 5-year survival using a publicly available transcriptomic dataset of a cervical cancer cohort. We report that poor prognosis in this cohort correlates with overexpression of a subset of stemness pathway genes, a majority of which regulate the central Focal Adhesion pathway, and are also found to be enriched in the HPV infection pathway. These observations support therapeutic targeting of stemness genes overexpressed by mucosal cells infected with high-risk HPVs.
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Affiliation(s)
- Megha Budhwani
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Samuel W Lukowski
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Sandro V Porceddu
- Cancer Services, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Ian H Frazer
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Janin Chandra
- Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia
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Moore KM, Desai A, Delgado BDL, Trabulo SMD, Reader C, Brown NF, Murray ER, Brentnall A, Howard P, Masterson L, Zammarchi F, Hartley JA, van Berkel PH, Marshall JF. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics 2020; 10:2930-2942. [PMID: 32194845 PMCID: PMC7053198 DOI: 10.7150/thno.38702] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm3) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.
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Affiliation(s)
- Kate M. Moore
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Ami Desai
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Bea de Luxán Delgado
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Sara Maria David Trabulo
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Claire Reader
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Nicholas F. Brown
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Elizabeth R. Murray
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Adam Brentnall
- Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventative Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Philip Howard
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Luke Masterson
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Francesca Zammarchi
- ADC Therapeutics (UK) Ltd, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - John A. Hartley
- Cancer Research UK Drug-DNA Interactions Research Group, University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, U.K
| | | | - John F. Marshall
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Ahmadpour S, Hosseinimehr SJ. Recent developments in peptide-based SPECT radiopharmaceuticals for breast tumor targeting. Life Sci 2019; 239:116870. [DOI: 10.1016/j.lfs.2019.116870] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/31/2022]
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43
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Reader CS, Vallath S, Steele CW, Haider S, Brentnall A, Desai A, Moore KM, Jamieson NB, Chang D, Bailey P, Scarpa A, Lawlor R, Chelala C, Keyse SM, Biankin A, Morton JP, Evans TRJ, Barry ST, Sansom OJ, Kocher HM, Marshall JF. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J Pathol 2019; 249:332-342. [PMID: 31259422 PMCID: PMC6852434 DOI: 10.1002/path.5320] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/22/2019] [Accepted: 06/21/2019] [Indexed: 12/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10-8 ). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Antineoplastic Agents, Immunological/pharmacology
- Apoptosis
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/secondary
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Dual Specificity Phosphatase 6/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Genes, ras
- Humans
- Integrases/genetics
- Integrins/antagonists & inhibitors
- Integrins/genetics
- Integrins/metabolism
- Italy
- Mice, Nude
- Mice, Transgenic
- Neoplasm Invasiveness
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Signal Transduction
- Tumor Burden
- Tumor Microenvironment
- United Kingdom
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Claire S Reader
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | - Sabari Vallath
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | | | | | - Adam Brentnall
- Centre for Cancer Prevention, Wolfson Institute of Preventive MedicineQueen Mary University of LondonLondonUK
| | - Ami Desai
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | - Kate M Moore
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | - Nigel B Jamieson
- Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life SciencesUniversity of Glasgow, Glasgow Royal InfirmaryGlasgowUK
- West of Scotland Pancreatic UnitGlasgow Royal InfirmaryGlasgowUK
| | - David Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Peter Bailey
- Wolfson Wohl Cancer Research Centre, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Aldo Scarpa
- ARC‐NET Research Centre for Applied Research on CancerUniversity of VeronaVeronaItaly
| | - Rita Lawlor
- ARC‐NET Research Centre for Applied Research on CancerUniversity of VeronaVeronaItaly
| | - Claude Chelala
- Centre for Molecular Oncology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | - Stephen M Keyse
- Division of Cancer Research, University of Dundee, James Arrott DriveNinewells Hospital and Medical SchoolDundeeUK
| | - Andrew Biankin
- Centre for Molecular Oncology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | | | - TR Jeffry Evans
- Cancer Research UK Beatson InstituteGlasgowUK
- Wolfson Wohl Cancer Research Centre, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | | | | | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of ExcellenceQueen Mary University of London, John Vane Science CentreLondonUK
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Rajabi M, Adeyeye M, Mousa SA. Peptide-Conjugated Nanoparticles as Targeted Anti-angiogenesis Therapeutic and Diagnostic in Cancer. Curr Med Chem 2019; 26:5664-5683. [DOI: 10.2174/0929867326666190620100800] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 03/11/2019] [Accepted: 03/21/2019] [Indexed: 12/25/2022]
Abstract
:Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progression (tumor growth arrest), which may be further reduced with the targetdelivered anticancer agent. This review provides an update of tumor vascular targeting for therapeutic and diagnostic applications, with conventional or long-circulating nanoparticles decorated with peptides that target neovascularization (anti-angiogenesis) in the tumor microenvironment.
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Affiliation(s)
- Mehdi Rajabi
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States
| | - Mary Adeyeye
- Department of Chemistry, University of Albany, State University of New York, Albany, NY 12222, United States
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States
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45
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Evaluation of integrin αvβ 6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. Nat Commun 2019; 10:4673. [PMID: 31611594 PMCID: PMC6791878 DOI: 10.1038/s41467-019-11863-w] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 08/06/2019] [Indexed: 12/13/2022] Open
Abstract
Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6. Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.
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Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment. Cancers (Basel) 2019; 11:cancers11091221. [PMID: 31438626 PMCID: PMC6769837 DOI: 10.3390/cancers11091221] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/12/2019] [Accepted: 08/15/2019] [Indexed: 12/26/2022] Open
Abstract
TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.
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47
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Łasiñska I, Mackiewicz J. Integrins as A New Target for Cancer Treatment. Anticancer Agents Med Chem 2019; 19:580-586. [DOI: 10.2174/1871520618666181119103413] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/16/2018] [Accepted: 11/10/2018] [Indexed: 12/19/2022]
Abstract
:Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments.:Integrins are responsible for intercellular adhesion and interaction with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans.
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Affiliation(s)
- Izabela Łasiñska
- Department of Medical and Experimental Oncology, Heliodor Swiecicki University Hospital, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Mackiewicz
- Department of Medical and Experimental Oncology, Heliodor Swiecicki University Hospital, Poznan University of Medical Sciences, Poznan, Poland
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48
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Whilding LM, Halim L, Draper B, Parente-Pereira AC, Zabinski T, Davies DM, Maher J. CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies. Cancers (Basel) 2019; 11:E674. [PMID: 31091832 PMCID: PMC6563120 DOI: 10.3390/cancers11050674] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/10/2019] [Indexed: 02/06/2023] Open
Abstract
Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors.
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Affiliation(s)
- Lynsey M Whilding
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Leena Halim
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Benjamin Draper
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Ana C Parente-Pereira
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - Tomasz Zabinski
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - David Marc Davies
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
| | - John Maher
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
- Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, London SE5 9RS, UK.
- Department of Immunology, Eastbourne Hospital, East Sussex BN21 2UD, UK.
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Jiang J, Li X, Yin X, Zhang J, Shi B. Association of low expression of E-cadherin and β-catenin with the progression of early stage human squamous cervical cancer. Oncol Lett 2019; 17:5729-5739. [PMID: 31186799 DOI: 10.3892/ol.2019.10266] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 12/21/2018] [Indexed: 12/17/2022] Open
Abstract
The precise involvement and mechanisms of human papilloma virus type 16 (HPV16) in epithelial-mesenchymal transition (EMT) of cervical intraepithelial neoplasia (CIN) and squamous cervical cancer (SCC) remain unknown. The present study aimed to examine the expression of EMT indicators and their association with HPV16 in CIN and early stage SCC, and their prognostic value in early stage SCC. The expression levels of E-cadherin, N-cadherin, β-catenin, vimentin, and fibronectin were determined by immunohistochemistry in 40 patients with normal uterine cervix, 22 patients with CIN1, 60 patients with CIN2-3, and 86 patients with SCC, stage Ia-IIa, according to the International Federation of Gynecology and Obstetrics. The expression of the epithelial indicators E-cadherin and β-catenin gradually declined, and the mesenchymal indicators N-cadherin, vimentin, and fibronectin increased with progression of the cervical lesions (P<0.05). Patients with SCC with lymph node metastasis, parametrial invasion, negative E-cadherin, and negative β-catenin expression had shorter overall survival (P=0.001, P=0.015, P=0.014, and P=0.043, respectively) and disease-free survival (P=0.002, P=0.021, P=0.025, and P=0.045, respectively) time. Multivariate survival analysis indicated that lymph node metastasis [Hazard ratio (HR)=3.544; P=0.010], parametrial invasion (HR=2.014; P=0.007) and E-cadherin expression (HR=0.163; P<0.001) were independently associated with overall survival, but also with disease-free survival (HR=3.612, P=0.009; HR=1.935, P=0.011; HR=0.168, P<0.001, respectively). In patients with CINs, HPV16 infection was negatively correlated with the expression of E-cadherin, and positively correlated with the expression of N-cadherin, vimentin, and fibronectin. EMT occurs during the progression of CINs to early stage SCC, and is associated with HPV16 infection in CINs. Lymph node metastasis and parametrial invasion are poor prognostic factors for SCC, while positive E-cadherin expression may serve as a protective prognostic factor for SCC.
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Affiliation(s)
- Jing Jiang
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xinling Li
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiangmei Yin
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Jieying Zhang
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Bin Shi
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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50
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Hausner SH, Bold RJ, Cheuy LY, Chew HK, Daly ME, Davis RA, Foster CC, Kim EJ, Sutcliffe JL. Preclinical Development and First-in-Human Imaging of the Integrin α vβ 6 with [ 18F]α vβ 6-Binding Peptide in Metastatic Carcinoma. Clin Cancer Res 2019; 25:1206-1215. [PMID: 30401687 PMCID: PMC6377828 DOI: 10.1158/1078-0432.ccr-18-2665] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/28/2018] [Accepted: 11/02/2018] [Indexed: 01/08/2023]
Abstract
PURPOSE The study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with PET. EXPERIMENTAL DESIGN The peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. RESULTS [18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin αvβ6 in vitro [IC50(αvβ6) = 1.2 nmol/L vs IC50(αvβ3) >10 μmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. CONCLUSIONS The clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.
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Affiliation(s)
- Sven H Hausner
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Davis and Sacramento, California
| | - Richard J Bold
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Davis and Sacramento, California
| | - Lina Y Cheuy
- Department of Biomedical Engineering, University of California Davis, Davis and Sacramento, California
| | - Helen K Chew
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Davis and Sacramento, California
| | - Megan E Daly
- Department of Radiation Oncology, University of California Davis, Davis and Sacramento, California
| | - Ryan A Davis
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Davis and Sacramento, California
| | - Cameron C Foster
- Division of Nuclear Medicine, Department of Radiology, University of California Davis, Davis and Sacramento, California
| | - Edward J Kim
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Davis and Sacramento, California
| | - Julie L Sutcliffe
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Davis and Sacramento, California.
- Department of Biomedical Engineering, University of California Davis, Davis and Sacramento, California
- Center for Molecular and Genomic Imaging, University of California Davis, Davis and Sacramento, California
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