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1
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Reuning U, D'Amore VM, Hodivala-Dilke K, Marinelli L, Kessler H. Importance of integrin transmembrane helical interactions for antagonistic versus agonistic ligand behavior: Consequences for medical applications. Bioorg Chem 2025; 156:108193. [PMID: 39842299 DOI: 10.1016/j.bioorg.2025.108193] [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: 08/08/2024] [Revised: 11/27/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
Integrins are well-characterized receptors involved in cell adhesion and signaling. With six approved drugs, they are recognized as valuable therapeutic targets. Here, we explore potential activation mechanisms that may clarify the agonist versus antagonist behavior of integrin ligands. The reorganization of the transmembrane domain (TMD) in the integrin receptor, forming homooligomers within focal adhesions, could be key to the understanding of the agonistic properties of integrin ligands at substoichiometric concentrations. This has significant implications for medical applications. While we focus on the RGD peptide-recognizing integrin subfamily, we propose that these mechanistic insights may also apply to other integrin subtypes. For application of integrin ligands in medicine it is essential to consider this mechanism and its consequences for affinity and bioavailability.
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Affiliation(s)
- Ute Reuning
- TUM University Hospital, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Department of Gynecology and Obstetrics, Clinical Research Unit, Ismaninger Strasse 22, 81675 Munich, Germany.
| | - Vincenzo Maria D'Amore
- University of Naples Federico II, UNINA-Department of Pharmacy, C.so Umberto I, 40, 80138 Naples, Italy.
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
| | - Luciana Marinelli
- University of Naples Federico II, UNINA-Department of Pharmacy, C.so Umberto I, 40, 80138 Naples, Italy.
| | - Horst Kessler
- Institute for Advanced Study, Department of Chemistry, School of Natural Sciences and Bavarian NMR Center (BNMRZ), Technical University Munich, Ernst-Otto-Fischer-Str. 2, 85748 Garching, Germany.
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2
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Ludwig B, Krautkremer N, Tomassi S, Di Maro S, Di Leva FS, Benge A, Nieberler M, Kessler H, Marinelli L, Kossatz S, Reuning U. Switching Roles─Exploring Concentration-Dependent Agonistic versus Antagonistic Behavior of Integrin Ligands. J Med Chem 2025; 68:4334-4351. [PMID: 39908297 PMCID: PMC11874007 DOI: 10.1021/acs.jmedchem.4c02111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/21/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025]
Abstract
Identification of integrins as cancer targets has stimulated the development of specific inhibitory ligands. However, following cilengitide's unexpected clinical failure by promoting angiogenesis at low concentrations, pure ligand antagonism was soon scrutinized. We evaluated αvβ3, αvβ6, or α5β1 ligands for concentration-dependent functional switches in respective integrin subtype-overexpressing cancer cells. Cilengitide (L2) or L1 provoked minor transient changes in (p)-FAK and (p)-p44/42(erk-1/2) predominantly at low concentrations and antagonized cell migration at high concentrations, while agonistically accelerating it at low concentrations. L5 (α5β1) showed bell-shaped FAK activation at both concentrations, blocking cell migration at high concentrations only in α5β1+ OV-MZ-6 cells, not acting agonistically. L3 (αvβ6) did not alter signaling upon long exposure but transiently and early activated FAK in αvβ6+ HN cells at both concentrations, with neither antagonistic nor agonistic consequences on cell motility. These data underscore the need for in-depth evaluation of ligand actions to ensure their most promising medical use.
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Affiliation(s)
- Beatrice
Stefanie Ludwig
- Department
of Nuclear Medicine, School of Medicine & Health, Klinikum rechts
der Isar, TUM University Hospital, Technical
University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
- Central Institute
for Translational Cancer Research (TranslaTUM), School of Medicine
& Health, Klinikum rechts der Isar, TUM University Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
| | - Nils Krautkremer
- Department
of Oral and Maxillofacial Surgery, School of Medicine & Health,
Klinikum rechts der Isar, TUM University
Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
| | - Stefano Tomassi
- UNINA
−
Department of Pharmacy, University of Naples
Federico II, Via Domenico Montesano 49, Naples 80131, Italy
| | - Salvatore Di Maro
- SUN −
Department of Environmental, Biological and Pharmaceutical Sciences
and Technologies, Università degli
Studi della Campania “Luigi Vanvitelli”, Viale Abramo Lincoln, 5, Caserta 81100, Italy
| | - Francesco Saverio Di Leva
- UNINA
−
Department of Pharmacy, University of Naples
Federico II, Via Domenico Montesano 49, Naples 80131, Italy
| | - Anke Benge
- Department
of Obstetrics & Gynecology, School of Medicine & Health, Clinical
Research Unit, Klinikum rechts der Isar, TUM University Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
| | - Markus Nieberler
- Department
of Oral and Maxillofacial Surgery, School of Medicine & Health,
Klinikum rechts der Isar, TUM University
Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
| | - Horst Kessler
- Department
of Chemistry, School of Natural Sciences and Bavarian NMR Center (BNMRZ), Institute for Advanced Study, Technical University
Munich, Lichtenbergstrasse
2a, Garching 85748, Germany
| | - Luciana Marinelli
- UNINA
−
Department of Pharmacy, University of Naples
Federico II, Via Domenico Montesano 49, Naples 80131, Italy
| | - Susanne Kossatz
- Department
of Nuclear Medicine, School of Medicine & Health, Klinikum rechts
der Isar, TUM University Hospital, Technical
University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
- Central Institute
for Translational Cancer Research (TranslaTUM), School of Medicine
& Health, Klinikum rechts der Isar, TUM University Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
- Department
of Chemistry, School of Natural Sciences, Technical University Munich, Ismaninger Strasse 22, Munich 81675, Germany
| | - Ute Reuning
- Department
of Obstetrics & Gynecology, School of Medicine & Health, Clinical
Research Unit, Klinikum rechts der Isar, TUM University Hospital, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany
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3
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Burčík D, Macko J, Podrojková N, Demeterová J, Stano M, Oriňak A. Role of Cell Adhesion in Cancer Metastasis Formation: A Review. ACS OMEGA 2025; 10:5193-5213. [PMID: 39989825 PMCID: PMC11840620 DOI: 10.1021/acsomega.4c08140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/10/2025] [Accepted: 01/22/2025] [Indexed: 02/25/2025]
Abstract
Intercellular adhesion is accompanied by several physical quantities and actions. In this review, we tried to collect information about the influence of surface energy and its impact on cell-cell adhesion. It still undergoes development for cancer treatment. Data on receptor-ligand interactions that occur on circulating tumor cells (CTCs) are described, and adhesion receptors as therapeutic targets are collected. Additionally, the impact of surface roughness on the interactions between CTC cells and the surface was monitored. The effects of different cell adhesion molecules (CAMs) on cell adhesion, growth, and proliferation were investigated. This review offers general principles of cell adhesion, through the blockade of adhesion with blocking drugs and inhibitors like computational models that describe the process of adhesion. Some theoretical models based on the minimum of the total free energy of interaction between CAMs and selected organic molecules have been presented. The final aim was to find information on how modulation of the surface of CTCs (by medicals or physically) inhibits cancer metastases formation.
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Affiliation(s)
- Denis Burčík
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
| | - Ján Macko
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
| | - Natália Podrojková
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
| | - Jana Demeterová
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
| | - Michal Stano
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
| | - Andrej Oriňak
- University of P. J. Safarik
in Kosice, Faculty of Sciences,
Institute of Chemistry, Department of Physical Chemistry, Moyzesova 11, 041 01 Kosice, Slovakia
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Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer. Cancers (Basel) 2023; 15:cancers15041216. [PMID: 36831558 PMCID: PMC9954089 DOI: 10.3390/cancers15041216] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/02/2023] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Human epidermal growth factor receptor-2 (HER2)-targeting therapies provide clinical benefits for patients with HER2-positive breast cancer. However, the resistance to monotherapies invariably develops and leads to disease relapse and treatment failure. Previous studies have demonstrated a link between the potency of HER2-targeting tyrosine kinase inhibitors (TKIs) and their ability to induce an iron-dependent form of cell death called ferroptosis. The aim of this study was to understand the mechanisms of resistance to TKI-induced ferroptosis and identify novel approaches to overcome treatment resistance. We used mouse and human HER2-positive models of acquired TKI resistance to demonstrate an intimate link between the resistance to TKIs and to ferroptosis and present the first evidence that the cell adhesion receptor αvβ3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that αvβ3 integrin-mediated resistance is associated with the re-wiring of the iron/antioxidant metabolism and persistent activation of AKT signalling. Moreover, using gene manipulation approaches and pharmacological inhibitors, we show that this "αvβ3 integrin addiction" can be targeted to reverse TKI resistance. Collectively, these findings provide critical insights into new therapeutic strategies to improve the treatment of advanced HER2-positive breast cancer patients.
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5
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Role of Anti-Angiogenic Factors in the Pathogenesis of Breast Cancer: A Review of Therapeutic Potential. Pathol Res Pract 2022; 236:153956. [DOI: 10.1016/j.prp.2022.153956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022]
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6
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Kim EY, Dryer SE. RAGE and αVβ3-integrin are essential for suPAR signaling in podocytes. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166186. [PMID: 34166766 DOI: 10.1016/j.bbadis.2021.166186] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 12/25/2022]
Abstract
The soluble urokinase plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney diseases including primary and recurrent focal and segmental glomerulosclerosis (FSGS), diabetic nephropathy, and acute kidney injuries (AKI). Elevated serum suPAR concentration is a negative prognostic indicator in multiple critical clinical conditions. This study has examined the initial transduction steps used by suPAR in cultured mouse podocytes. We now report that the receptor for advanced glycation end-products (RAGE) co-immunoprecipitates with αV and β3 integrin subunits, which have been previously shown to initiate suPAR signal transduction at the podocyte cell surface. siRNA knock-down of RAGE attenuated Src phosphorylation evoked by either suPAR or by glycated albumin (AGE-BSA), a prototypical RAGE agonist. suPAR effects on Src phosphorylation were also blocked by the structurally dissimilar RAGE antagonists FPS-ZM1 and azeliragon, as well as by cilengitide, an inhibitor of outside-in signaling through αV-integrins. FPS-ZM1 also blocked Src phosphorylation evoked by AGE-BSA. FPS-ZM1 blocked increases in cell surface TRPC6 abundance, cytosolic reactive oxygen species (ROS) and activation of the small GTPase Rac1 evoked by either suPAR or AGE-BSA. In addition, FPS-ZM1 inhibited Src phosphorylation evoked by serum collected from a patient with recurrent FSGS during a relapse. The magnitude of this inhibition was indistinguishable from the effect produced by a neutralizing antibody against suPAR. These data suggest that orally bioavailable small molecule RAGE antagonists could represent a useful therapeutic strategy for a wide range of clinical conditions associated with elevated serum suPAR, including primary FSGS and AKI.
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Affiliation(s)
- Eun Young Kim
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
| | - Stuart E Dryer
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA; Department of Biomedical Sciences, University of Houston College of Medicine, Houston, TX 77204, USA.
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7
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Soltantoyeh T, Akbari B, Karimi A, Mahmoodi Chalbatani G, Ghahri-Saremi N, Hadjati J, Hamblin MR, Mirzaei HR. Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead. Cells 2021; 10:cells10061450. [PMID: 34207884 PMCID: PMC8230324 DOI: 10.3390/cells10061450] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma.
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Affiliation(s)
- Tahereh Soltantoyeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Amirali Karimi
- School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran;
| | - Ghanbar Mahmoodi Chalbatani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Navid Ghahri-Saremi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa;
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
- Correspondence: ; Tel.: +98-21-64053268; Fax: +98-21-66419536
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8
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Presle A, Frémont S, Salles A, Commere PH, Sassoon N, Berlioz-Torrent C, Gupta-Rossi N, Echard A. The viral restriction factor tetherin/BST2 tethers cytokinetic midbody remnants to the cell surface. Curr Biol 2021; 31:2203-2213.e5. [PMID: 33711249 DOI: 10.1016/j.cub.2021.02.039] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 01/18/2021] [Accepted: 02/16/2021] [Indexed: 11/17/2022]
Abstract
The midbody at the center of the intercellular bridge connecting dividing cells recruits the machinery essential for the final steps of cytokinesis.1-5 Successive abscission on both sides of the midbody generates a free midbody remnant (MBR) that can be inherited and accumulated in many cancer, immortalized, and stem cells, both in culture and in vivo.6-12 Strikingly, this organelle was recently shown to contain information that induces cancer cell proliferation, influences cell polarity, and promotes dorso-ventral axis specification upon interaction with recipient cells.13-16 Yet the mechanisms by which the MBR is captured by either a daughter cell or a distant cell are poorly described.10,14 Here, we report that BST2/tetherin, a well-established restriction factor that blocks the release of numerous enveloped viruses from the surface of infected cells,17-20 plays an analogous role in retaining midbody remnants. We found that BST2 is enriched at the midbody during cytokinesis and localizes at the surface of MBRs in a variety of cells. Knocking out BST2 induces the detachment of MBRs from the cell surface, their accumulation in the extracellular medium, and their transfer to distant cells. Mechanistically, the localization of BST2 at the MBR membrane is both necessary and sufficient for the interaction between MBRs and the cell surface. We thus propose that BST2 tethers post-cytokinetic midbody remnants to the cell surface. This finding reveals new parallels between cytokinesis and viral biology21-26 that unexpectedly extend beyond the ESCRT-dependent abscission step.
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Affiliation(s)
- Adrien Presle
- Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, CNRS, 25-28 rue du Dr Roux, 75015 Paris, France; Sorbonne Université, Collège Doctoral, 75005 Paris, France
| | - Stéphane Frémont
- Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, CNRS, 25-28 rue du Dr Roux, 75015 Paris, France
| | - Audrey Salles
- UTechS Photonic BioImaging PBI (Imagopole), Centre de Recherche et de Ressources Technologiques C2RT, Institut Pasteur, 75015 Paris, France
| | - Pierre-Henri Commere
- UTechS CB, Centre de Recherche et de Ressources Technologiques C2RT, Institut Pasteur, 75015 Paris, France
| | - Nathalie Sassoon
- Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, CNRS, 25-28 rue du Dr Roux, 75015 Paris, France
| | | | - Neetu Gupta-Rossi
- Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, CNRS, 25-28 rue du Dr Roux, 75015 Paris, France
| | - Arnaud Echard
- Membrane Traffic and Cell Division Lab, Institut Pasteur, UMR3691, CNRS, 25-28 rue du Dr Roux, 75015 Paris, France.
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9
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Polani F, Grierson PM, Lim KH. Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects. World J Gastroenterol 2021; 27:2105-2121. [PMID: 34025067 PMCID: PMC8117738 DOI: 10.3748/wjg.v27.i18.2105] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/09/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
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Affiliation(s)
- Faran Polani
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Patrick M Grierson
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
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10
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Ludwig BS, Kessler H, Kossatz S, Reuning U. RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. Cancers (Basel) 2021; 13:1711. [PMID: 33916607 PMCID: PMC8038522 DOI: 10.3390/cancers13071711] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/22/2021] [Accepted: 03/29/2021] [Indexed: 12/19/2022] Open
Abstract
Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.
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Affiliation(s)
- Beatrice S. Ludwig
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research (TranslaTUM), Technical University Munich, 81675 Munich, Germany;
| | - Horst Kessler
- Department of Chemistry, Institute for Advanced Study, Technical University Munich, 85748 Garching, Germany;
| | - Susanne Kossatz
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar and Central Institute for Translational Cancer Research (TranslaTUM), Technical University Munich, 81675 Munich, Germany;
- Department of Chemistry, Institute for Advanced Study, Technical University Munich, 85748 Garching, Germany;
| | - Ute Reuning
- Clinical Research Unit, Department of Obstetrics and Gynecology, University Hospital Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany
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11
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Liu S, Ren J, Ten Dijke P. Targeting TGFβ signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6:8. [PMID: 33414388 PMCID: PMC7791126 DOI: 10.1038/s41392-020-00436-9] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/04/2020] [Accepted: 12/05/2020] [Indexed: 12/19/2022] Open
Abstract
Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.
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Affiliation(s)
- Sijia Liu
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Jiang Ren
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands.
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12
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Ritzenthaler JD, Zhang M, Torres-Gonzalez E, Roman J. The Integrin Inhibitor Cilengitide and Bleomycin-Induced Pulmonary Fibrosis : Cilengitide and Bleomycin-Induced Pulmonary Fibrosis. Lung 2020; 198:947-955. [PMID: 33146772 DOI: 10.1007/s00408-020-00400-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/18/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE Fibroproliferation and excess deposition of extracellular matrix (ECM) are the pathologic hallmarks of idiopathic pulmonary fibrosis (IPF), a chronic progressive disorder with high mortality and suboptimal treatment options. Although the etiologic mechanisms responsible for the development and progression of IPF remain unclear, cell-ECM interactions and growth factors are considered important. Cilengitide is a cyclic RGD pentapeptide with anti-angiogenic activity that targets αvβ3, αvβ5 and α5β1, integrins known to mediate cell-ECM interactions and activate the pro-fibrotic growth factor Transforming Growth Factor beta (TGF-β). METHODS Cilengitide was studied in vitro with the use of NIH/3T3 cells and primary lung fibroblasts, and in vivo in the well-characterized bleomycin-induced lung injury model. The extent of ECM deposition was determined by RT-PCR, Western blot, histologic analysis and hydroxyproline assay of lung tissue. Bronchoalveolar lavage analysis was used to determine cell counts. RESULTS Cilengitide treatment of cultured fibroblasts showed decreased adhesion to vitronectin and fibronectin, both integrin-dependent events. Cilengitide also inhibited TGF-β-induced fibronectin gene expression and reduced the accumulation of mRNAs and protein for fibronectin and collagen type I. Both preventive and treatment effects of daily injections of cilengitide (20 mg/kg) failed to inhibit the development of pulmonary fibrosis as determined by histological analysis (Ashcroft scoring), bronchoalveolar lavage (BAL) fluid cell counts, and hydroxyproline content. CONCLUSIONS Overall, our data suggest that, despite its in vitro activity in fibroblasts, daily injections of cilengitide (20 mg/kg) did not inhibit the development of or ameliorate bleomycin-induced pulmonary fibrosis in mice.
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Affiliation(s)
- Jeffrey D Ritzenthaler
- Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA.
| | - Michael Zhang
- Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.,University of Minnesota Medical School, Minneapolis, MN, USA
| | - Edilson Torres-Gonzalez
- Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA
| | - Jesse Roman
- Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.,Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA.,Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
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13
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Modulating Tumor Cell Functions by Tunable Nanopatterned Ligand Presentation. NANOMATERIALS 2020; 10:nano10020212. [PMID: 31991896 PMCID: PMC7074906 DOI: 10.3390/nano10020212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/19/2022]
Abstract
Cancer comprises a large group of complex diseases which arise from the misrouted interplay of mutated cells with other cells and the extracellular matrix. The extracellular matrix is a highly dynamic structure providing biochemical and biophysical cues that regulate tumor cell behavior. While the relevance of biochemical signals has been appreciated, the complex input of biophysical properties like the variation of ligand density and distribution is a relatively new field in cancer research. Nanotechnology has become a very promising tool to mimic the physiological dimension of biophysical signals and their positive (i.e., growth-promoting) and negative (i.e., anti-tumoral or cytotoxic) effects on cellular functions. Here, we review tumor-associated cellular functions such as proliferation, epithelial-mesenchymal transition (EMT), invasion, and phenotype switch that are regulated by biophysical parameters such as ligand density or substrate elasticity. We also address the question of how such factors exert inhibitory or even toxic effects upon tumor cells. We describe three principles of nanostructured model systems based on block copolymer nanolithography, electron beam lithography, and DNA origami that have contributed to our understanding of how biophysical signals direct cancer cell fate.
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Xu Y, Sun L, Feng S, Chen J, Gao Y, Guo L, An X, Nie Y, Zhang Y, Liu X, Ning X. Smart pH-Sensitive Nanogels for Enhancing Synergistic Anticancer Effects of Integrin α vβ 3 Specific Apoptotic Peptide and Therapeutic Nitric Oxide. ACS APPLIED MATERIALS & INTERFACES 2019; 11:34663-34675. [PMID: 31490654 DOI: 10.1021/acsami.9b10830] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Apoptotic peptide (kla), which can trigger the mitochondria-mediated apoptotic programmed cell death, has been widely recognized as a potential anticancer agent. However, its therapeutic potential has been significantly impaired by its poor biostability, lack of tumor specificity, and particularly low cellular uptake. Herein, a linear peptide Arg-Trp-d-Arg-Asn-Arg (RWrNR) was identified as an integrin αvβ3 specific ligand with a nanomolar dissociation constant (Kd = 0.95 nM), which can greatly improve kla antitumor activity (IC50 = 8.81 μM) by improving its cellular uptake, compared to the classic integrin-recognition motif c-RGDyK (IC50 = 37.96 μM). Particularly, the RWrNR-kla conjugate can be entrapped in acidic sensitive nanogels (RK/Parg/CMCS-NGs), composed of poly-l-arginine (Parg) and carboxymethyl chitosan (CMCS, pI = 6.8), which can not only carry out controlled release of RWrNR-kla in response to the tumor acidic microenvironment, and consequently enhance its tumor specificity and cell internalization, but also trigger tumor-associated macrophages to generate nitric oxide, leading to enhanced synergistic anticancer efficacy. Importantly, RK/Parg/CMCS-NGs have been proven to effectively activate the apoptosis signaling pathway in vivo and significantly inhibit tumor growth with minimal adverse effects. To summarize, RK/Parg/CMCS-NGs are a promising apoptotic peptide-based therapeutics with enhanced tumor accumulation, cytosolic delivery, and synergistic anticancer effects, thereby holding great potential for the treatment of malignant tumors.
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Affiliation(s)
- Yurui Xu
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Lei Sun
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Shujun Feng
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Jianmei Chen
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Ya Gao
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Leilei Guo
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials , China Pharmaceutical University , Nanjing 210009 , China
| | - Xueying An
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital , The Affiliated Hospital of Nanjing University Medical School , Nanjing 210093 , China
| | - Yuanyuan Nie
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Yu Zhang
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
| | - Xiaoxuan Liu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials , China Pharmaceutical University , Nanjing 210009 , China
| | - Xinghai Ning
- National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China
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Peterman E, Gibieža P, Schafer J, Skeberdis VA, Kaupinis A, Valius M, Heiligenstein X, Hurbain I, Raposo G, Prekeris R. The post-abscission midbody is an intracellular signaling organelle that regulates cell proliferation. Nat Commun 2019; 10:3181. [PMID: 31320617 PMCID: PMC6639393 DOI: 10.1038/s41467-019-10871-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 06/01/2019] [Indexed: 01/05/2023] Open
Abstract
Once thought to be a remnant of cell division, the midbody (MB) has recently been shown to have roles beyond its primary function of orchestrating abscission. Despite the emerging roles of post-abscission MBs, how MBs accumulate in the cytoplasm and signal to regulate cellular functions remains unknown. Here, we show that extracellular post-abscission MBs can be internalized by interphase cells, where they reside in the cytoplasm as a membrane-bound signaling structure that we have named the MBsome. We demonstrate that MBsomes stimulate cell proliferation and that MBsome formation is a phagocytosis-like process that depends on a phosphatidylserine/integrin complex, driven by actin-rich membrane protrusions. Finally, we show that MBsomes rely on dynamic actin coats to slow lysosomal degradation and propagate their signaling function. In summary, MBsomes may sometimes serve as intracellular organelles that signal via integrin and EGFR-dependent pathways to promote cell proliferation and anchorage-independent growth and survival.
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Affiliation(s)
- Eric Peterman
- Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Paulius Gibieža
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, 44307, Lithuania
| | - Johnathon Schafer
- Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | | | - Algirdas Kaupinis
- Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Vilnius University, Vilnius, 10257, Lithuania
| | - Mindaugas Valius
- Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Vilnius University, Vilnius, 10257, Lithuania
| | - Xavier Heiligenstein
- Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, 75005, France
| | - Ilse Hurbain
- Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, 75005, France
- Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, 75005, France
| | - Graca Raposo
- Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, 75005, France
- Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, 75005, France
| | - Rytis Prekeris
- Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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THPep: A machine learning-based approach for predicting tumor homing peptides. Comput Biol Chem 2019; 80:441-451. [PMID: 31151025 DOI: 10.1016/j.compbiolchem.2019.05.008] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/18/2019] [Accepted: 05/17/2019] [Indexed: 01/24/2023]
Abstract
In the present era, a major drawback of current anti-cancer drugs is the lack of satisfactory specificity towards tumor cells. Despite the presence of several therapies against cancer, tumor homing peptides are gaining importance as therapeutic agents. In this regard, the huge number of therapeutic peptides generated in recent years, demands the need to develop an effective and interpretable computational model for rapidly, effectively and automatically predicting tumor homing peptides. Therefore, a sequence-based approach referred herein as THPep has been developed to predict and analyze tumor homing peptides by using an interpretable random forest classifier in concomitant with amino acid composition, dipeptide composition and pseudo amino acid composition. An overall accuracy and Matthews correlation coefficient of 90.13% and 0.76, respectively, were achieved from the independent test set on an objective benchmark dataset. Upon comparison, it was found that THPep was superior to the existing method and holds high potential as a useful tool for predicting tumor homing peptides. For the convenience of experimental scientists, a web server for this proposed method is provided publicly at http://codes.bio/thpep/.
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17
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Cruz da Silva E, Dontenwill M, Choulier L, Lehmann M. Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer. Cancers (Basel) 2019; 11:cancers11050692. [PMID: 31109009 PMCID: PMC6562376 DOI: 10.3390/cancers11050692] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.
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Affiliation(s)
- Elisabete Cruz da Silva
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Monique Dontenwill
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Laurence Choulier
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Maxime Lehmann
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
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18
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Wang T, Huang J, Vue M, Alavian MR, Goel HL, Altieri DC, Languino LR, FitzGerald TJ. α vβ 3 Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin. Mol Cancer Res 2018; 17:398-408. [PMID: 30266752 DOI: 10.1158/1541-7786.mcr-18-0544] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 08/03/2018] [Accepted: 09/19/2018] [Indexed: 01/08/2023]
Abstract
The αvβ3 integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of αvβ3 integrin on the radiosensitivity of prostate cancer cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with αvβ3 integrin and PC-3 cells that contain endogenous β3 integrin were used. This study demonstrated that αvβ3 integrin increases survival of αvβ3-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of αvβ3 integrin in PC-3 cells sensitizes to radiation. Expression of αvβ3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αvβ3 integrin in PC-3 cells inhibits anchorage-independent cell growth. The αvβ3 antagonist, cRGD, significantly increases radiosensitivity in both αvβ3-LNCaP and PC-3 cells. Moreover, αvβ3 integrin prevents radiation-induced downregulation of survivin. Inhibition of survivin expression by siRNA or shRNA enhances IR-induced inhibition of anchorage-independent cell growth. Overexpression of wild-type survivin in PC-3 cells treated with αvβ3 integrin shRNA increases survival of cells upon IR. These findings reveal that αvβ3 integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting αvβ3 integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.
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Affiliation(s)
- Tao Wang
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Jiayi Huang
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Mai Vue
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Michael R Alavian
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Dario C Altieri
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Lucia R Languino
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Thomas J FitzGerald
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts.
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19
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Hatley RJD, Macdonald SJF, Slack RJ, Le J, Ludbrook SB, Lukey PT. An αv-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities. Angew Chem Int Ed Engl 2018; 57:3298-3321. [DOI: 10.1002/anie.201707948] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Richard J. D. Hatley
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
| | - Simon J. F. Macdonald
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
| | - Robert J. Slack
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
| | - Joelle Le
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
| | - Steven B. Ludbrook
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
| | - Pauline T. Lukey
- Fibrosis DPU; Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY UK
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20
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Hatley RJD, Macdonald SJF, Slack RJ, Le J, Ludbrook SB, Lukey PT. Ein Instrumentarium von αv-RGD-Integrin-Inhibitoren: Wirkstoffsuche, Herausforderungen und Möglichkeiten. Angew Chem Int Ed Engl 2018. [DOI: 10.1002/ange.201707948] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Richard J. D. Hatley
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
| | - Simon J. F. Macdonald
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
| | - Robert J. Slack
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
| | - Joelle Le
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
| | - Steven B. Ludbrook
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
| | - Pauline T. Lukey
- Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area; GlaxoSmithKline Medicines Research Centre; Gunnels Wood Road Stevenage SG1 2NY Großbritannien
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21
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Massabeau C, Khalifa J, Filleron T, Modesto A, Bigay-Gamé L, Plat G, Dierickx L, Aziza R, Rouquette I, Gomez-Roca C, Mounier M, Delord JP, Toulas C, Olivier P, Chatelut E, Mazières J, Cohen-Jonathan Moyal E. Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non-Small-cell Lung Cancer: A Phase I Study. Clin Lung Cancer 2017; 19:e277-e285. [PMID: 29221762 DOI: 10.1016/j.cllc.2017.11.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 10/18/2017] [Accepted: 11/10/2017] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.
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Affiliation(s)
- Carole Massabeau
- Department of Radiation Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Jonathan Khalifa
- Department of Radiation Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France.
| | - Thomas Filleron
- Department of Biostatistics, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Anouchka Modesto
- Department of Radiation Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Laurence Bigay-Gamé
- Department of Pneumology, Centre Hospitalo-Universitaire Larrey, Toulouse, France
| | - Gavin Plat
- Department of Pneumology, Centre Hospitalo-Universitaire Larrey, Toulouse, France
| | - Lawrence Dierickx
- Department of Imaging/Nuclear Medicine, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Richard Aziza
- Department of Imaging/Nuclear Medicine, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Isabelle Rouquette
- Department of Pathology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Carlos Gomez-Roca
- Department of Medical Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Muriel Mounier
- Department of Biostatistics, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Jean-Pierre Delord
- Department of Medical Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1037, Centre de Recherche Contre le Cancer de Toulouse, Toulouse, France
| | - Christine Toulas
- INSERM U1037, Centre de Recherche Contre le Cancer de Toulouse, Toulouse, France
| | - Pascale Olivier
- Vigilance des Essais Cliniques, de la recherche et de l'innovation du Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Etienne Chatelut
- Université Paul Sabatier, Toulouse, France; INSERM U1037, Centre de Recherche Contre le Cancer de Toulouse, Toulouse, France; Laboratoire de Pharmacologie, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France
| | - Julien Mazières
- Department of Pneumology, Centre Hospitalo-Universitaire Larrey, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1037, Centre de Recherche Contre le Cancer de Toulouse, Toulouse, France
| | - Elizabeth Cohen-Jonathan Moyal
- Department of Radiation Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse, Oncopole, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1037, Centre de Recherche Contre le Cancer de Toulouse, Toulouse, France
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Abstract
Background: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors. Methods: We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years. Results: Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing. Conclusions: The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed.
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Affiliation(s)
- Nicholas Butowski
- Department of Neurological Surgery, University of California, San Francisco, CA 94143-0350, USA
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23
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Raab-Westphal S, Marshall JF, Goodman SL. Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel) 2017; 9:E110. [PMID: 28832494 PMCID: PMC5615325 DOI: 10.3390/cancers9090110] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 08/11/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.
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Affiliation(s)
- Sabine Raab-Westphal
- Translational In Vivo Pharmacology, Translational Innovation Platform Oncology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
| | - John F Marshall
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
| | - Simon L Goodman
- Translational and Biomarkers Research, Translational Innovation Platform Oncology, Merck KGaA, 64293 Darmstadt, Germany.
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First plasma and tissue pharmacokinetic study of the YSNSG cyclopeptide, a new integrin antagonist, using microdialysis. Eur J Pharm Sci 2017; 105:178-187. [DOI: 10.1016/j.ejps.2017.05.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 05/08/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022]
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25
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S Franco S, Szczesna K, Iliou MS, Al-Qahtani M, Mobasheri A, Kobolák J, Dinnyés A. In vitro models of cancer stem cells and clinical applications. BMC Cancer 2016; 16:738. [PMID: 27766946 PMCID: PMC5073996 DOI: 10.1186/s12885-016-2774-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called “cancer stem cells” (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours. The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review.
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Affiliation(s)
- Sara S Franco
- Szent István University, Gödöllö, Hungary.,Biotalentum Ltd., Gödöllö, Hungary
| | | | - Maria S Iliou
- Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mohammed Al-Qahtani
- Center of Excellence in Genomic Medicine Research (CEGMR), King AbdulAziz University, Jeddah, Kingdom of Saudi Arabia
| | - Ali Mobasheri
- Center of Excellence in Genomic Medicine Research (CEGMR), King AbdulAziz University, Jeddah, Kingdom of Saudi Arabia.,Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
| | | | - András Dinnyés
- Szent István University, Gödöllö, Hungary. .,Biotalentum Ltd., Gödöllö, Hungary. .,Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
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26
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Qian DC, Xiao X, Byun J, Suriawinata AA, Her SC, Amos CI, Barth RJ. PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer. Clin Cancer Res 2016; 23:399-406. [PMID: 27435399 DOI: 10.1158/1078-0432.ccr-16-0623] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 06/20/2016] [Accepted: 07/12/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. EXPERIMENTAL DESIGN Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane-related functions. RESULTS There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%). CONCLUSIONS Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399-406. ©2016 AACR.
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Affiliation(s)
- David C Qian
- Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire
| | - Xiangjun Xiao
- Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire
| | - Jinyoung Byun
- Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire
| | - Arief A Suriawinata
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Stephanie C Her
- Department of Computer Science, Dartmouth College, Hanover, New Hampshire
| | - Christopher I Amos
- Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
| | - Richard J Barth
- Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
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27
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Adhesion molecules and the extracellular matrix as drug targets for glioma. Brain Tumor Pathol 2016; 33:97-106. [PMID: 26992378 DOI: 10.1007/s10014-016-0261-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/07/2016] [Indexed: 12/14/2022]
Abstract
The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.
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28
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Dolgos H, Freisleben A, Wimmer E, Scheible H, Krätzer F, Yamagata T, Gallemann D, Fluck M. In vitro and in vivo drug disposition of cilengitide in animals and human. Pharmacol Res Perspect 2016; 4:e00217. [PMID: 27069630 PMCID: PMC4804314 DOI: 10.1002/prp2.217] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 12/11/2015] [Accepted: 12/30/2015] [Indexed: 02/04/2023] Open
Abstract
Cilengitide is very low permeable (1.0 nm/sec) stable cyclic pentapeptide containing an Arg-Gly-Asp motif responsible for selective binding to αvβ3 and αvβ5 integrins administered intravenously (i.v.). In vivo studies in the mouse and Cynomolgus monkeys showed the major component in plasma was unchanged drug (>85%). These results, together with the absence of metabolism in vitro and in animals, indicate minimal metabolism in both species. The excretion of [(14)C]-cilengitide showed profound species differences, with a high renal excretion of the parent drug observed in Cynomolgus monkey (50% dose), but not in mouse (7 and 28%: m/f). Consistently fecal (biliary) secretion was high in mouse (87 and 66% dose: m/f) but low in Cynomolgus monkey (36.5%). Human volunteers administrated with [(14)C]-cilengitide showed that most of the dose was recovered in urine as unchanged drug (77.5%, referred to Becker et al. 2015), indicating that the Cynomolgus monkey was the closer species to human. In order to better understand the species difference between human and mouse, the hepatobiliary disposition of [(14)C]-cilengitide was determined in sandwich-cultured hepatocytes. Cilengitide exhibited modest biliary efflux (30-40%) in mouse, while in human hepatocytes this was negligible. Furthermore, it was confirmed that the uptake of cilengitide into human hepatocytes was minor and appeared to be passive. In summary, the extent of renal and biliary secretion of cilengitide appears to be highly species specific and is qualitatively well explained using sandwich hepatocyte culture models.
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Affiliation(s)
- Hugues Dolgos
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Achim Freisleben
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Elmar Wimmer
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Holger Scheible
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Friedrich Krätzer
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Tetsuo Yamagata
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Dieter Gallemann
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
| | - Markus Fluck
- Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD) Merck Grafing Germany
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29
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Castañeda-Gill JM, Vishwanatha JK. Antiangiogenic mechanisms and factors in breast cancer treatment. J Carcinog 2016; 15:1. [PMID: 27013929 PMCID: PMC4785777 DOI: 10.4103/1477-3163.176223] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is known to metastasize in its latter stages of existence. The different angiogenic mechanisms and factors that allow for its progression are reviewed in this article. Understanding these mechanisms and factors will allow researchers to design drugs to inhibit angiogenic behaviors and control the rate of tumor growth.
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Affiliation(s)
- Jessica M. Castañeda-Gill
- Department of Molecular and Medical Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Jamboor K. Vishwanatha
- Department of Molecular and Medical Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA
- Institute for Cancer Research, Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, USA
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30
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Withofs N, Hustinx R. Integrin αvβ3 and RGD-based radiopharmaceuticals. MEDECINE NUCLEAIRE-IMAGERIE FONCTIONNELLE ET METABOLIQUE 2016. [DOI: 10.1016/j.mednuc.2015.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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31
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Farina B, de Paola I, Russo L, Capasso D, Liguoro A, Gatto AD, Saviano M, Pedone PV, Di Gaetano S, Malgieri G, Zaccaro L, Fattorusso R. A Combined NMR and Computational Approach to Determine the RGDechi-hCit-αv β3 Integrin Recognition Mode in Isolated Cell Membranes. Chemistry 2015; 22:681-93. [PMID: 26548575 DOI: 10.1002/chem.201503126] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Indexed: 11/07/2022]
Abstract
The critical role of integrins in tumor progression and metastasis has stimulated intense efforts to identify pharmacological agents that can modulate integrin function. In recent years, αv β3 and αv β5 integrin antagonists were demonstrated to be effective in blocking tumor progression. RGDechi-hCit, a chimeric peptide containing a cyclic RGD motif linked to an echistatin C-terminal fragment, is able to recognize selectively αv β3 integrin both in vitro and in vivo. High-resolution molecular details of the selective αv β3 recognition of the peptide are certainly required, nonetheless RGDechi-hCit internalization limited the use of classical in cell NMR experiments. To overcome such limitations, we used WM266 isolated cellular membranes to accomplish a detailed NMR interaction study that, combined with a computational analysis, provides significant structural insights into αv β3 molecular recognition by RGDechi-hCit. Remarkably, on the basis of the identified molecular determinants, we design a RGDechi-hCit mutant that is selective for αv β5 integrin.
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Affiliation(s)
- Biancamaria Farina
- Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy).,Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Ivan de Paola
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Luigi Russo
- Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy)
| | - Domenica Capasso
- Dipartimento di Farmacia, Università di Napoli Federico II, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Annamaria Liguoro
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Annarita Del Gatto
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Michele Saviano
- Istituto di Cristallografia, CNR, Via Amendola 122/O, 70126 Bari (Italy)
| | - Paolo V Pedone
- Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy)
| | - Sonia Di Gaetano
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy)
| | - Gaetano Malgieri
- Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy)
| | - Laura Zaccaro
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Naples (Italy).
| | - Roberto Fattorusso
- Dipatimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi Napoli, Via Vivaldi 46, 81100, Caserta (Italy).
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32
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Gounder MM, Nayak L, Sahebjam S, Muzikansky A, Sanchez AJ, Desideri S, Ye X, Ivy SP, Nabors LB, Prados M, Grossman S, DeAngelis LM, Wen PY. Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors. J Clin Oncol 2015; 33:3186-92. [PMID: 26282642 DOI: 10.1200/jco.2015.61.1525] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
PURPOSE Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. PATIENT AND METHODS Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. RESULTS Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, <one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade≥3 nonhematologic and grade≥4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. CONCLUSION Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.
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Affiliation(s)
- Mrinal M Gounder
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
| | - Lakshmi Nayak
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Solmaz Sahebjam
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Alona Muzikansky
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Armando J Sanchez
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Serena Desideri
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Xiaobu Ye
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - S Percy Ivy
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - L Burt Nabors
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Michael Prados
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Stuart Grossman
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Lisa M DeAngelis
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
| | - Patrick Y Wen
- Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA
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Abstract
Bone metastasis is a common burden in many types of cancer and has a severe impact on the quality of life in patients. Hence, specific therapeutic strategies inhibiting tumor induced osteolysis are urgently needed. In this study, we aimed to interfere with integrin adhesion receptors, which are central players of the bone resorption process. For this purpose, we used cilengitide, a cyclic RGD peptide, which blocks integrin αVβ3 and αVβ5-ligand binding. Our results revealed that cilengitide blocked osteoclast maturation in a dose-dependent manner. In detail, pre-osteoclasts treated with cilengitide exhibited reduced cell spreading, cell migration and cell adhesion on RGD-containing matrix proteins, which are ligands of integrin αV. The activation of the most upstream signal transduction molecules of the integrin receptor-initiated pathway, FAK and c-Src, were consistently blocked by cilengitide. First evidence suggests that cilengitide might interfere with metastatic bone disease in vivo and this study describes a potential underlying mechanism of the inhibitory effect of cilengitide on αV-integrin expressing pre-osteoclasts by blocking integrin ligand binding and interfering with osteoclast maturation and cell behavior. In conclusion, our findings suggest that cilengitide, which interferes with αV-integrins on osteoclasts, may represent a novel therapeutic strategy in the treatment of malignant bone disease.
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Browne A, Tookman LA, Ingemarsdotter CK, Bouwman RD, Pirlo K, Wang Y, McNeish IA, Lockley M. Pharmacological Inhibition of β3 Integrin Reduces the Inflammatory Toxicities Caused by Oncolytic Adenovirus without Compromising Anticancer Activity. Cancer Res 2015; 75:2811-21. [PMID: 25977332 DOI: 10.1158/0008-5472.can-14-3761] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 04/07/2015] [Indexed: 01/28/2023]
Abstract
Adenoviruses have been clinically tested as anticancer therapies but their utility has been severely limited by rapid, systemic cytokine release and consequent inflammatory toxicity. Here, we describe a new approach to tackling these dangerous side effects. Using human ovarian cancer cell lines as well as malignant epithelial cells harvested from the ascites of women with ovarian cancer, we show that tumor cells do not produce cytokines in the first 24 hours following in vitro infection with the oncolytic adenovirus dl922-947. In contrast, dl922-947 does induce inflammatory cytokines at early time points following intraperitoneal delivery in mice with human ovarian cancer intraperitoneal xenografts. In these animals, cytokines originate predominantly in murine tissues, especially in macrophage-rich organs such as the spleen. We use a nonreplicating adenovirus to confirm that early cytokine production is independent of adenoviral replication. Using β3 integrin knockout mice injected intraperitoneally with dl922-947 and β3 null murine peritoneal macrophages, we confirm a role for macrophage cell surface β3 integrin in this dl922-947-induced inflammation. We present new evidence that co-administration of a cyclic RGD-mimetic-specific inhibitor of β3 integrin significantly attenuates the cytokine release and inflammatory hepatic toxicity induced by dl922-947 in an intraperitoneal murine model of ovarian cancer. Importantly, we find no evidence that β3 inhibition compromises viral infectivity and oncolysis in vitro or anticancer efficacy in vivo. By enabling safe, systemic delivery of replicating adenoviruses, this novel approach could have a major impact on the future development of these effective anticancer agents.
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Affiliation(s)
- Ashley Browne
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Laura A Tookman
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Carin K Ingemarsdotter
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Russell D Bouwman
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Katrina Pirlo
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Yaohe Wang
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Iain A McNeish
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom. Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Michelle Lockley
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
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35
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Abstract
The treatment of bone-metastatic cancer now takes advantage of the unique biology of this clinical state. The complex interplay between the cancer cells and the bone microenvironment leads to a host of therapeutic targets, with agents in various stages of clinical use or study. Targets include interactions between the cancer cells and osteoclasts, osteoblasts, endothelial cells, stromal cells, hematopoietic progenitor cells, cells of the immune system, and the bone matrix. Efforts at understanding specific mechanisms of drug resistance in the bone are also ongoing. Successful clinical outcomes will be the result of co-targeting and interrupting the various tumor-supportive elements and cooperating pathways at the level of the tumor cell, the primary and metastatic microenvironments, and systemic cancer effects, leading to a "scaled network disruption" to undermine the disease state.
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Affiliation(s)
- Daniel F Camacho
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 7431 CCC 1500 E Medical Ctr, Ann Arbor, MI, 48109, USA
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36
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Becker A, von Richter O, Kovar A, Scheible H, van Lier JJ, Johne A. Metabolism and disposition of the αv-integrin ß3/ß5 receptor antagonist cilengitide, a cyclic polypeptide, in humans. J Clin Pharmacol 2015; 55:815-24. [PMID: 25683324 DOI: 10.1002/jcph.482] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 02/06/2015] [Indexed: 01/02/2023]
Abstract
Cilengitide (EMD 121974, manufactured by Merck KGaA, Darmstadt, Germany) is an αv-integrin receptor antagonist showing high affinity for αvβ3 and αvβ5.This study determined the mass balance of cilengitide in healthy volunteers receiving a single intravenous infusion of 2.1 MBq (14) C-cilengitide spiked into 250 mL of 2000 mg of cilengitide. Blood, urine, and feces were collected up to day 15 or until excretion of radioactivity was below 1% of the administered dose. Total radioactivity derived from the administration of (14) C-cilengitide and unlabeled cilengitide levels were determined and used for calculation of pharmacokinetic parameters.(14) C-cilengitide-related radioactivity was completely recovered (94.5%; 87.4%-100.6%) and was mainly excreted into urine (mean, 79.0%; range, 70.3%-88.2%) and to a lesser extent into feces (mean, 15.5%; range, 9.3%-20.3%). Of the administered dose, 77.5% was recovered as unchanged cilengitide in urine. The concentration profiles of cilengitide and total radioactivity in plasma were comparable. No circulating metabolites were identified in plasma and urine. Two metabolites,M606-1 and M606-2, were identified in feces considered to be formed by intestinal peptidases or by peptidases from fecal bacteria. In conclusion, the data show that following intravenous administration, (14) C-cilengitide was completely recovered, was excreted mainly via renal elimination, and was not metabolized systemically.
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Affiliation(s)
- Andreas Becker
- Merck Serono-Global Early Development, Department of Clinical Pharmacology, Merck KGaA, Darmstadt, Germany
| | - Oliver von Richter
- Merck Serono-Global Early Development, Department of Clinical Pharmacology, Merck KGaA, Darmstadt, Germany
| | | | - Holger Scheible
- Merck Serono-Global Early Development, Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany
| | - Jan J van Lier
- Pharmaceutical Research Association (PRA), Zuidlaren, The Netherlands
| | - Andreas Johne
- Merck Serono-Global Early Development, Department of Clinical Pharmacology, Merck KGaA, Darmstadt, Germany
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Toporkiewicz M, Meissner J, Matusewicz L, Czogalla A, Sikorski AF. Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges. Int J Nanomedicine 2015; 10:1399-414. [PMID: 25733832 PMCID: PMC4337502 DOI: 10.2147/ijn.s74514] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
There are many problems directly correlated with the systemic administration of drugs and how they reach their target site. Targeting promises to be a hopeful strategy as an improved means of drug delivery, with reduced toxicity and minimal adverse side effects. Targeting exploits the high affinity of cell-surface-targeted ligands, either directly or as carriers for a drug, for specific retention and uptake by the targeted diseased cells. One of the most important parameters which should be taken into consideration in the selection of an appropriate ligand for targeting is the binding affinity (K D). In this review we focus on the importance of binding affinities of monoclonal antibodies, antibody derivatives, peptides, aptamers, DARPins, and small targeting molecules in the process of selection of the most suitable ligand for targeting of nanoparticles. In order to provide a critical comparison between these various options, we have also assessed each technology format across a range of parameters such as molecular size, immunogenicity, costs of production, clinical profiles, and examples of the level of selectivity and toxicity of each. Wherever possible, we have also assessed how incorporating such a targeted approach compares with, or is superior to, original treatments.
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Affiliation(s)
- Monika Toporkiewicz
- Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Justyna Meissner
- Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Lucyna Matusewicz
- Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Aleksander Czogalla
- Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Aleksander F Sikorski
- Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
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38
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Liu C, Yang Y, Chen L, Lin YL, Li F. A unified mechanism for aminopeptidase N-based tumor cell motility and tumor-homing therapy. J Biol Chem 2014; 289:34520-9. [PMID: 25359769 DOI: 10.1074/jbc.m114.566802] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tumor cell surface aminopeptidase N (APN or CD13) has two puzzling functions unrelated to its enzymatic activity: mediating tumor cell motility and serving as a receptor for tumor-homing peptides (peptides that bring anti-cancer drugs to tumor cells). To investigate APN-based tumor-homing therapy, we determined the crystal structure of APN complexed with a tumor-homing peptide containing a representative Asn-Gly-Arg (NGR) motif. The tumor-homing peptide binds to the APN enzymatic active site, but it resists APN degradation due to a distorted scissile peptide bond. To explore APN-based tumor cell motility, we examined the interactions between APN and extracellular matrix (ECM) proteins. APN binds to, but does not degrade, NGR motifs in ECM proteins that share similar conformations with the NGR motif in the APN-bound tumor-homing peptide. Therefore, APN-based tumor cell motility and tumor-homing therapy rely on a unified mechanism in which both functions are driven by the specific and stable interactions between APN and the NGR motifs in ECM proteins and tumor-homing peptides. This study further implicates APN as an integrin-like molecule that functions broadly in cell motility and adhesion by interacting with its signature NGR motifs in the extracellular environment.
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Affiliation(s)
- Chang Liu
- From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Yang Yang
- From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Lang Chen
- From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Yi-Lun Lin
- From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
| | - Fang Li
- From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
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Amschler K, Erpenbeck L, Kruss S, Schön MP. Nanoscale integrin ligand patterns determine melanoma cell behavior. ACS NANO 2014; 8:9113-25. [PMID: 25171587 DOI: 10.1021/nn502690b] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cells use integrin receptors to adhere onto surfaces by binding to ligands such as the arginine-glycine-aspartic acid (RGD) motif. Cancer cells make use of this adhesion process, which has motivated the development of integrin-directed drugs. However, those drugs may exert paradoxical effects on tumor progression, which raises the question of how integrin function is governed in tumor cells on the nanoscale. We have utilized precisely defined and tunable RGD ligand site densities spanning 1 order of magnitude, i.e., 103 to 1145 ligand sites/μm(2), by using RGD-functionalized gold nanoparticle patterns immobilized on glass by block copolymer (micellar) nanolithography. In an αVβ3 integrin-dependent fashion, human melanoma cells spread, formed focal contacts, and reorganized cytoskeletal fibers on a physiologically relevant RGD density of 349 sites/μm(2). Intriguingly, low doses of solute RGD "shifted" the optimal densities of immobilized ligand along with corresponding melanoma cell integrin clusters and cytoskeletal changes toward those typical for "intermediate" ligand presentation. Consequently, melanoma cells were forced into a "permissive" state, optimizing interactions with suboptimal nanostructured biomimetic surfaces, thus providing an explanation for the seemingly paradoxical effects on tumor progression and a potential clue for individualized antitumoral therapies.
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Affiliation(s)
- Katharina Amschler
- Department of Dermatology, Venereology and Allergology, Georg August University , Göttingen, Germany
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40
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Bojić M, Barbero L, Dolgos H, Freisleben A, Gallemann D, Riva S, Guengerich FP. Time- and NADPH-dependent inhibition of cytochrome P450 3A4 by the cyclopentapeptide cilengitide: significance of the guanidine group and accompanying spectral changes. Drug Metab Dispos 2014; 42:1438-46. [PMID: 24985702 DOI: 10.1124/dmd.114.059295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Cilengitide is a stable cyclic pentapeptide containing an Arg-Gly-Asp motif responsible for selective binding to αVβ3 and αVβ5 integrins. The candidate drug showed unexpected inhibition of cytochrome P450 (P450) 3A4 at high concentrations, that is, a 15-mM concentration caused attenuation of P450 3A4 activity (depending on the probe substrate): 15-19% direct inhibition, 10-23% time-dependent inhibition (30-minute preincubation), and 54-60% metabolism-dependent inhibition (30-minute preincubation). The inactivation efficiency determined with human liver microsomes was 0.003 ± 0.001 min(-1) mM(-1) and was 0.04 ± 0.01 min(-1) mM(-1) with baculovirus-based microsomes containing recombinant P450 3A4. Neither heme loss nor covalent binding to apoprotein could explain the observed reductions in residual activity. Slowly forming type II difference spectra were observed, with maximum spectral changes after 2 hours. Binding to both reduced and oxidized P450 3A4 was observed, with apparent Kd values of 0.66 μM and 6 μM. The significance of the guanidine group in inhibition was demonstrated using ligand binding spectral changes and inactivation assays with guanidine analogs (debrisoquine, N-acetylarginine-O-methyl ester) and the acetylated ornithine derivative of cilengitide. The observed inhibition could be explained by direct inhibition, plus by formation of stable complexes with both ferric and ferrous forms of heme iron and to some extent by the formation of reactive species capable to react to the protein or heme. Formation of the complex required time and NADPH and is attributed to the guanidino group. Thus, the NADPH-dependent inhibition is considered to be mainly due to the formation of a stable complex rather than the formation of reactive species.
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Affiliation(s)
- Mirza Bojić
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - Luca Barbero
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - Hugues Dolgos
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - Achim Freisleben
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - Dieter Gallemann
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - Simona Riva
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
| | - F Peter Guengerich
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (M.B., F.P.G.); Merck-Serono, RBM S.p.A. Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa, Torino, Italy (L.B., S.R.); Merck-Serono, Global Early Development, Darmstadt, Germany (H.D.); and Merck-Serono, Global Early Development, Darmstadt/Global DMPK, Grafing, Germany (A.F., D.G.)
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Batich KA, Sampson JH. Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens. Expert Opin Pharmacother 2014; 15:2047-61. [PMID: 25139628 DOI: 10.1517/14656566.2014.947266] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Malignant gliomas (MGs) represent the most common primary brain tumors in adults, the most deadly of which is grade IV glioblastoma. Patients with glioblastoma undergoing current standard-of-care therapy have a median survival of 12 - 15 months. AREAS COVERED Over the past 25 years, there have been modest advancements in the treatment of MGs. Assessment of therapeutic responses has continued to evolve to account for the increasing number of agents being tested in the clinic. Currently approved therapies for primary tumors have been extended for use in the setting of recurrent disease with modest efficacy. Agents initially approved for recurrent gliomas have begun to demonstrate efficacy against de novo tumors but will ultimately need to be evaluated in future studies for scheduling, timing and dosing relative to chemotherapy. EXPERT OPINION Screening and identification of tumor-specific mutations is critical for the advancement of effective therapy that is both safe and precise for the patient. Two unique antigens found in glioblastoma are currently being employed as targets for immunotherapeutic vaccines, one of which has advanced to Phase III testing. Whole genome sequencing of MGs has yielded two other novel mutations that offer great promise for the development of molecular inhibitors.
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Affiliation(s)
- Kristen A Batich
- Duke University Medical Center, Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery , DUMC Box 3050, 303 Research Drive, 220 Sands Building, Durham, NC 27710 , USA +1 919 684 9041 ; +1 919 684 9045 ;
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42
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Zühlsdorf M, Bhattaram VA, Campioni M, Krösser S, Derendorf H, Kovar A. Population pharmacokinetics of cilengitide in adult and pediatric cancer patients from a nonlinear mixed-effects analysis. J Clin Pharmacol 2014; 54:1391-9. [PMID: 24911832 DOI: 10.1002/jcph.343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 06/04/2014] [Indexed: 11/06/2022]
Abstract
Cilengitide is an αvβ3/αvβ5-integrin inhibitor investigated as an anticancer agent. This study aimed to develop a cilengitide population pharmacokinetic model using nonlinear mixed-effects modeling of 136 adult patients with advanced solid tumors and to scale the pharmacokinetic parameters to the pediatric population. A stepwise approach was used, beginning with exploratory analyses checking database/target covariate relationships. A two-compartment structural model was developed to describe cilengitide's concentration-time profile and assess covariates' impact on pharmacokinetic parameters. A bootstrap procedure validated the base/final model stability. A two-compartment model best described concentration-time data. Estimated structural model parameters were: 2.79 L h(-) (1) m(-) (2) central compartment mean systemic clearance, 6.75 L m(-) (2) central compartment volume of distribution, 1.3 L h(-) (1) m(-) (2) intercompartmental clearance, and 3.85 L m(-) (2) peripheral compartment volume of distribution. Mean half-life was 0.9 and 3.8 h (α/β-phase). Co-medications and study populations had no impact, as the different studies were not significant model covariates. Weight and body surface area correlated with the pharmacokinetic parameters (r = 0.95, P < 0.01). Pharmacokinetic parameters were consistent with individual study-derived parameters; their allometric scaling enabled pediatric pharmacokinetic profile predictions as corroborated by independent data. This model provides the basis for pharmacokinetic profile simulations of different dosages/regimens in different populations.
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Affiliation(s)
- Michael Zühlsdorf
- Translational Innovation Platform Oncology, Merck KGaA, Darmstadt, Germany
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43
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Affiliation(s)
- David A Cheresh
- From the Departments of Pathology (D.A.C.) and Reproductive Medicine (D.G.S.), University of California San Diego School of Medicine, San Diego, CA; and Moores Cancer Center, La Jolla, CA (D.A.C., D.G.S.)
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44
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Aladowicz E, Ferro L, Vitali GC, Venditti E, Fornasari L, Lanfrancone L. Molecular networks in melanoma invasion and metastasis. Future Oncol 2013; 9:713-26. [PMID: 23647299 DOI: 10.2217/fon.13.9] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Metastatic melanoma accounts for approximately 80% of skin cancer-related deaths. Up to now there has been no effective treatment for stage IV melanoma patients due to the complexity and dissemination potential of this disease. Melanomas are heterogeneous tumors in which conventional therapies fail to improve overall survival. Targeted therapies are being developed, but the final outcome can be hampered by the incomplete knowledge of the process of melanoma progression. Even if the intracellular pathways are similar, the interaction of the cells with the surrounding environment should be taken into consideration. This article seeks to highlight some of the advances in the understanding of the molecular mechanisms underlying melanoma dissemination.
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Affiliation(s)
- Ewa Aladowicz
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan, Italy
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45
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Onishi M, Kurozumi K, Ichikawa T, Date I. Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme. Neurol Med Chir (Tokyo) 2013; 53:755-63. [PMID: 24162241 PMCID: PMC4508716 DOI: 10.2176/nmc.ra2013-0200] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma invasion and angiogenesis mechanisms will lead to the development of potential new treatments. In this review, we focus on the molecular characteristics of angiogenesis and invasion in human malignant glioma. We discuss bevacizumab and cilengitide, which are used to inhibit angiogenesis in GBM.
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Affiliation(s)
- Manabu Onishi
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
- Address reprint requests to: Manabu Onishi, MD, PhD, Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Okayama 700-8558, Japan. e-mail:
| | - Kazuhiko Kurozumi
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
| | - Tomotsugu Ichikawa
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
| | - Isao Date
- Department of Neurological Surgery, Okayama, University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama
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MacDonald TJ, Vezina G, Stewart CF, Turner D, Pierson CR, Chen L, Pollack IF, Gajjar A, Kieran MW. Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: a report from the Children's Oncology Group. Neuro Oncol 2013; 15:1438-44. [PMID: 24014381 DOI: 10.1093/neuonc/not058] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cilengitide, an αv integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population. METHODS Cilengitide (1800 mg/m(2)/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1-20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point. RESULTS Toxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11-114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28-325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively. CONCLUSIONS We conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded.
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Affiliation(s)
- Tobey J MacDonald
- Corresponding Author: Tobey J. MacDonald, MD, Emory Children's Center, Aflac Cancer and Blood Disorders Center, 2015 Uppergate Drive NE, Suite 442, Atlanta, GA 30322.
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Patil SA, Hosni-Ahmed A, Jones TS, Patil R, Pfeffer LM, Miller DD. Novel approaches to glioma drug design and drug screening. Expert Opin Drug Discov 2013; 8:1135-51. [PMID: 23738794 DOI: 10.1517/17460441.2013.807248] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Gliomas are considered the most malignant form of brain tumors, and ranked among the most aggressive human cancers. Despite advance standard therapy the prognosis for patients with gliomas remains poor. Chemotherapy has played an important role as an adjuvant in treating gliomas. The efficacy of the chemotherapeutic drug is limited due to poor drug delivery and the inherent chemo- and radio-resistance. Challenges of the brain cancer therapy in clinical settings are; i) to overcome the chemo- and radio-resistance, ii) to improve drug delivery to tumors and iii) the development of effective drug screening procedures. AREAS COVERED In this review, the authors discuss clinically important chemotherapeutic agents used for treating malignant gliomas along with novel drug design approaches. The authors, furthermore, discuss the in vitro and in vivo drug screening procedures for the development of novel drug candidates. EXPERT OPINION The development of novel and highly potent chemotherapeutic agents for both glioma and glioma stem cells (GSCs) is highly important for future brain cancer research. Thus, research efforts should be directed towards developing innovative molecularly targeted antiglioma agents in order to reduce the toxicity and drug resistance which are associated with current forms of therapy. Development of novel pre-clinical drug screening procedures is also very critical for the overall success of brain cancer therapies in clinical settings.
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Affiliation(s)
- Shivaputra A Patil
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 847 Monroe Avenue, Room 327, 881 Madison, Room 435, Memphis, TN 38163, USA.
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Berman AE, Kozlova NI, Morozevich GE. [Integrins as a potential target for targeted anticancer therapy]. BIOMEDITSINSKAIA KHIMIIA 2013; 59:239-248. [PMID: 23987064 DOI: 10.18097/pbmc20135903239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The review briefly summarizes information of structure of integrins and their involvement in the development and malignant progression of tumors. Special attention is paid to approaches based on modification of functional properties of integrins that prevent/antagonize tumor growth and progression; these approaches developed in modem experimental biology have certain perspective in clinical application.
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Dosanjh A, Robison E, Mondala T, Head SR, Salomon DR, Kurian SM. Genomic meta-analysis of growth factor and integrin pathways in chronic kidney transplant injury. BMC Genomics 2013; 14:275. [PMID: 23617750 PMCID: PMC3644490 DOI: 10.1186/1471-2164-14-275] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 04/18/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Chronic Allograft Nephropathy (CAN) is a clinical entity of progressive kidney transplant injury. The defining histology is tubular atrophy with interstitial fibrosis (IFTA). Using a meta-analysis of microarrays from 84 kidney transplant biopsies, we revealed growth factor and integrin adhesion molecule pathways differentially expressed and correlated with histological progression. A bioinformatics approach mining independent datasets leverages new and existing data to identify correlative changes in integrin and growth factor signaling pathways. RESULTS Analysis of CAN/IFTA Banff grades showed that hepatocyte growth factor (HGF), and epidermal growth factor (EGF) pathways are significantly differentially expressed in all classes of CAN/IFTA. MAPK-dependent pathways were also significant. However, the TGFβ pathways, albeit present, failed to differentiate CAN/IFTA progression. The integrin subunits β8, αv, αμ and β5 are differentially expressed, but β1, β6 and α6 specifically correlate with progression of chronic injury. Results were validated using our published proteomic profiling of CAN/IFTA. CONCLUSIONS CAN/IFTA with chronic kidney injury is characterized by expression of distinct growth factors and specific integrin adhesion molecules as well as their canonical signaling pathways. Drug target mapping suggests several novel candidates for the next generation of therapeutics to prevent or treat progressive transplant dysfunction with interstitial fibrosis.
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Affiliation(s)
- Amrita Dosanjh
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
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Bábíčková J, Tóthová Ľ, Boor P, Celec P. In vivo phage display--a discovery tool in molecular biomedicine. Biotechnol Adv 2013; 31:1247-59. [PMID: 23623852 DOI: 10.1016/j.biotechadv.2013.04.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 04/15/2013] [Accepted: 04/15/2013] [Indexed: 12/13/2022]
Abstract
In vivo phage display is a high-throughput method for identifying target ligands specific for different vascular beds. Targeting is possible due to the heterogeneous expression of receptors and other antigens in a particular vascular bed. Such expression is additionally influenced by the physiological or pathological status of the vasculature. In vivo phage display represents a technique that is usable in both, vascular mapping and targeted drug development. In this review, several important methodological aspects of in vivo phage display experiments are discussed. These include choosing an appropriate phage library, an appropriate animal model and the route of phage library administration. In addition, peptides or antibodies identified by in vivo phage display homing to specific types of vascular beds, including the altered vasculature present in several types of diseases are summarized. Still, confirmation in independent experiments and reproduction of identified sequences are needed for enhancing the clinical applicability of in vivo phage display research.
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Affiliation(s)
- Janka Bábíčková
- Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia; Division of Nephrology, RWTH University, Aachen, Germany
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