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Knop S, Szarejko M, Grząśko N, Bringhen S, Trautmann‐Grill K, Jurczyszyn A, Vacca A, Khandanpour C, Gamberi B, Pour L, Iversen KF, Stumpp MT, Suter C, Dawson KM, Zitt C, Legenne P, Stavropoulou V, Fey MF, Leupin N, Goldschmidt H. A phase 1b/2 study evaluating efficacy and safety of MP0250, a designed ankyrin repeat protein (DARPin) simultaneously targeting vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), in combination with bortezomib and dexamethasone, in patients with relapsed or refractory multiple myeloma. EJHAEM 2024; 5:940-950. [PMID: 39415900 PMCID: PMC11474421 DOI: 10.1002/jha2.968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 10/19/2024]
Abstract
MP0250 is a designed ankyrin repeat protein that specifically inhibits both vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor (HGF), aiming at potentiating cancer therapy by disrupting the tumour microenvironment. Encouraging results from a phase 1 trial of MP0250 in patients with solid tumours prompted further investigation in multiple myeloma (MM) as both MP0250 targets are reported to be drivers of MM pathogenesis. In this open-label, single-arm phase 1b/2 study (NCT03136653) in patients with proteasome inhibitor- and/or immunomodulatory drug-relapsed or refractory MM, MP0250 was administered every 3 weeks with standard bortezomib/dexamethasone regimen. Thirty-three patients received at least one dose of MP0250. The most frequent treatment-related adverse events were arterial hypertension (58.1%), thrombocytopenia (32.3%), proteinuria (29.0%) and peripheral oedema (19.4%). Of the 28 patients evaluable for response (median age: 60 [range 44-75]), nine achieved at least partial response, corresponding to an overall response rate of 32.1% (95% confidence interval [CI]: 17.9%, 50.7%), with a median duration of response of 8 months (95% CI 5-NR). An additional three patients achieved minimal response and nine stable diseases as the best overall response. Overall median progression-free survival was 4.2 months (95% CI 1.9-7.1). These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.
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Affiliation(s)
- Stefan Knop
- Universitätsklinikum WürzburgWürzburgGermany
| | | | - Norbert Grząśko
- Department of Experimental HematooncologyMedical University of Lublin and Centrum Onkologii Ziemi LubelskiejLublinPoland
| | - Sara Bringhen
- SSD Clinical Trial in Oncoematologia e Myeloma, Dipartimento di OncologiaAzienda Ospedaliera‐Universitaria Città della Salute e della Scienza di TorinoTorinoItaly
| | | | - Artur Jurczyszyn
- Plasma Cell Dyscrasias Center, Department of HematologyJagiellonian University Medical CollegeKrakowPoland
| | - Angelo Vacca
- Department of Precision and Regenerative Medicine and Ionian Area Unit of Medicina Interna “Guido Baccelli”University of Bari Aldo MoroAzienda PoliclinicoBariItaly
| | - Cyrus Khandanpour
- Universitätsklinikum Münster, Münster, Germany and University Hospital Schleswig‐Holstein Campus LübeckUniversity Cancer Center Schleswig‐Holstein, and University of LübeckLübeckGermany
| | | | | | | | | | - Cosima Suter
- Molecular Partners AGZurich‐SchlierenSwitzerland
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Wang C, Su NW, Hsu K, Kao CW, Chang MC, Chang YF, Lim KH, Chiang YH, Chang YC, Sung MT, Wu HH, Chen CG. The implication of serum HLA-G in angiogenesis of multiple myeloma. Mol Med 2024; 30:86. [PMID: 38877399 PMCID: PMC11177474 DOI: 10.1186/s10020-024-00860-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/10/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM. METHODS We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells. RESULTS We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN. CONCLUSION These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.
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Affiliation(s)
- Chi Wang
- Department of Laboratory Medicine, MacKay Memorial Hospital, New Taipei, 25160, Taiwan
| | - Nai-Wen Su
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Nursing, and Management, MacKay Junior College of Medicine, New Taipei, 25245, Taiwan
| | - Kate Hsu
- Nursing, and Management, MacKay Junior College of Medicine, New Taipei, 25245, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, 25245, Taiwan
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
| | - Chen-Wei Kao
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
| | - Ming-Chih Chang
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
| | - Yi-Fang Chang
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
| | - Ken-Hong Lim
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
| | - Yi-Hao Chiang
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
| | - Yu-Cheng Chang
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
| | - Meng-Ta Sung
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Hsueh-Hsia Wu
- Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, 110, Taiwan
| | - Caleb G Chen
- Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan.
- Nursing, and Management, MacKay Junior College of Medicine, New Taipei, 25245, Taiwan.
- Department of Hematology, GCRC Laboratory, Mackay Memorial Hospital, New Taipei City, 25160, Taiwan.
- Institute of Molecular Medicine, National Tsing-Hua University, Hsin-Chu, Taiwan.
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García-Sánchez D, González-González A, Alfonso-Fernández A, Del Dujo-Gutiérrez M, Pérez-Campo FM. Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression. World J Stem Cells 2023; 15:421-437. [PMID: 37342223 PMCID: PMC10277973 DOI: 10.4252/wjsc.v15.i5.421] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/27/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Ana Alfonso-Fernández
- Servicio de Traumatología y Cirugía Ortopédica, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Facultad de Medicina, Universidad de Cantabria, Santander 39008, Cantabria, Spain
| | - Mónica Del Dujo-Gutiérrez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
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Lamanuzzi A, Saltarella I, Reale A, Melaccio A, Solimando AG, Altamura C, Tamma G, Storlazzi CT, Tolomeo D, Desantis V, Mariggiò MA, Desaphy JF, Spencer A, Vacca A, Apollonio B, Frassanito MA. Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications. Biomedicines 2023; 11:biomedicines11051400. [PMID: 37239071 DOI: 10.3390/biomedicines11051400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs' cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies.
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Affiliation(s)
- Aurelia Lamanuzzi
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Ilaria Saltarella
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Antonia Reale
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University-Alfred Health, Melbourne, VIC 3004, Australia
| | - Assunta Melaccio
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Antonio Giovanni Solimando
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Concetta Altamura
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Grazia Tamma
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Clelia Tiziana Storlazzi
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Doron Tolomeo
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Vanessa Desantis
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Maria Addolorata Mariggiò
- Unit of Clinical Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Jean-François Desaphy
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Andrew Spencer
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University-Alfred Health, Melbourne, VIC 3004, Australia
- Malignant Haematology and Stem Cell Transplantation, Department of Haematology, Alfred Hospital, Melbourne, VIC 3004, Australia
- Department of Clinical Hematology, Monash University, Melbourne, VIC 3004, Australia
| | - Angelo Vacca
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Benedetta Apollonio
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- Unit of Clinical Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
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Saltarella I, Altamura C, Campanale C, Laghetti P, Vacca A, Frassanito MA, Desaphy JF. Anti-Angiogenic Activity of Drugs in Multiple Myeloma. Cancers (Basel) 2023; 15:cancers15071990. [PMID: 37046651 PMCID: PMC10093708 DOI: 10.3390/cancers15071990] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/20/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients’ prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting the importance of inhibiting angiogenesis from potentiating the antimyeloma activity. Here, we review the most important anti-angiogenic therapies used for the management of MM patients with a particular focus on their pharmacological profile and on their anti-angiogenic effect in vitro and in vivo. Despite the promising perspective, the direct targeting of angiogenic cytokines/receptors did not show a great efficacy in MM patients, suggesting the need to a deeper knowledge of the BM angiogenic niche for the design of novel multi-targeting anti-angiogenic therapies.
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Affiliation(s)
- Ilaria Saltarella
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Concetta Altamura
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Carmen Campanale
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Paola Laghetti
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Clinical Pathology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Jean-François Desaphy
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
- Correspondence:
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Saltarella I, Apollonio B, Lamanuzzi A, Desantis V, Mariggiò MA, Desaphy JF, Vacca A, Frassanito MA. The Landscape of lncRNAs in Multiple Myeloma: Implications in the "Hallmarks of Cancer", Clinical Perspectives and Therapeutic Opportunities. Cancers (Basel) 2022; 14:cancers14081963. [PMID: 35454868 PMCID: PMC9032822 DOI: 10.3390/cancers14081963] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Multiple myeloma (MM) is an aggressive hematological neoplasia caused by the uncontrolled proliferation of aberrant plasmacells. Neoplastic transformation and progression are driven by a number of biological processes, called ‘hallmarks of cancer’, which are regulated by different molecules, including long non-coding RNAs. A deeper understanding of the mechanisms that regulate MM development and progression will help to improve patients stratification and management, and promote the identification of new therapeutic targets. Abstract Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as “hallmarks of cancer” that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting.
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Affiliation(s)
- Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy; (I.S.); (B.A.); (A.L.); (V.D.); (A.V.)
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy;
| | - Benedetta Apollonio
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy; (I.S.); (B.A.); (A.L.); (V.D.); (A.V.)
| | - Aurelia Lamanuzzi
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy; (I.S.); (B.A.); (A.L.); (V.D.); (A.V.)
| | - Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy; (I.S.); (B.A.); (A.L.); (V.D.); (A.V.)
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy;
| | - Maria Addolorata Mariggiò
- Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari Aldo Moro, I-70124 Bari, Italy;
| | - Jean-François Desaphy
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy;
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, Piazza Giulio Cesare 11, I-70124 Bari, Italy; (I.S.); (B.A.); (A.L.); (V.D.); (A.V.)
| | - Maria Antonia Frassanito
- Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari Aldo Moro, I-70124 Bari, Italy;
- Correspondence:
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Melaccio A, Sgaramella LI, Pasculli A, Di Meo G, Gurrado A, Prete FP, Vacca A, Ria R, Testini M. Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer. Cancers (Basel) 2021; 13:2775. [PMID: 34204889 PMCID: PMC8199761 DOI: 10.3390/cancers13112775] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 12/15/2022] Open
Abstract
Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community's effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target.
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Affiliation(s)
- Assunta Melaccio
- Operative Unit of Internal Medicine “G. Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (A.M.); (A.V.); (R.R.)
| | - Lucia Ilaria Sgaramella
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
| | - Alessandro Pasculli
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
| | - Giovanna Di Meo
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
| | - Angela Gurrado
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
| | - Francesco Paolo Prete
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
| | - Angelo Vacca
- Operative Unit of Internal Medicine “G. Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (A.M.); (A.V.); (R.R.)
| | - Roberto Ria
- Operative Unit of Internal Medicine “G. Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (A.M.); (A.V.); (R.R.)
| | - Mario Testini
- Academic General Surgery Unit “V. Bonomo”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (L.I.S.); (A.P.); (G.D.M.); (A.G.); (F.P.P.)
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Ria R, Melaccio A, Racanelli V, Vacca A. Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients. J Clin Med 2020; 9:E1765. [PMID: 32517267 PMCID: PMC7355441 DOI: 10.3390/jcm9061765] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023] Open
Abstract
The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.
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Affiliation(s)
- Roberto Ria
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (A.M.); (V.R.); (A.V.)
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9
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A Comprehensive Biological and Clinical Perspective Can Drive a Patient-Tailored Approach to Multiple Myeloma: Bridging the Gaps between the Plasma Cell and the Neoplastic Niche. JOURNAL OF ONCOLOGY 2020; 2020:6820241. [PMID: 32508920 PMCID: PMC7251466 DOI: 10.1155/2020/6820241] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/17/2020] [Accepted: 04/10/2020] [Indexed: 12/13/2022]
Abstract
There is a broad spectrum of diseases labeled as multiple myeloma (MM). This is due not only to the composite prognostic risk factors leading to different clinical outcomes and responses to treatments but also to the composite tumor microenvironment that is involved in a vicious cycle with the MM plasma cells. New therapeutic strategies have improved MM patients' chances of survival. Nevertheless, certain patients' subgroups have a particularly unfavorable prognosis. Biological stratification can be subdivided into patient, disease, or therapy-related factors. Alternatively, the biological signature of aggressive disease and dismal therapeutic response can promote a dynamic, comprehensive strategic approach, better tailoring the clinical management of high-risk profiles and refractoriness to therapy and taking into account the role played by the MM milieu. By means of an extensive literature search, we have reviewed the state-of-the-art pathophysiological insights obtained from translational investigations of the MM-bone marrow microenvironment. A good knowledge of the MM niche pathophysiological dissection is crucial to tailor personalized approaches in a bench-bedside fashion. The discussion in this review pinpoints two main aspects that appear fundamental in order to gain novel and definitive results from the biology of MM. A systematic knowledge of the plasma cell disorder, along with greater efforts to face the unmet needs present in MM evolution, promises to open a new therapeutic window looking out onto the plethora of scientific evidence about the myeloma and the bystander cells.
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10
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Ria R, Vacca A. Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma. Int J Mol Sci 2020; 21:ijms21020613. [PMID: 31963513 PMCID: PMC7013615 DOI: 10.3390/ijms21020613] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 01/06/2023] Open
Abstract
Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.
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Affiliation(s)
- Roberto Ria
- Correspondence: ; Tel.: +39-080-559-31-06; Fax: +39-080-559-38-04
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11
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Abstract
Multiple myeloma (MM) is a lethal malignancy arising from plasma cells. MM cells experience endoplasmic reticulum (ER) stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1α mitigates ER stress by expanding protein-folding and secretion capacity, while supporting proteasomal degradation of ER misfolded proteins. IRE1α elaborates these functions by deploying a cytoplasmic kinase–RNase module to activate the transcription factor XBP1s. Although IRE1α has been implicated in MM, its validity as a potential therapeutic target—particularly as a kinase—has been unclear. Using genetic and pharmacologic disruption, we demonstrate that the IRE1α–XBP1s pathway is critical for MM tumor growth. We further show that the kinase domain of IRE1α is an effective and safe potential small-molecule target for MM therapy. Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase–endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α–XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138− cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.
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12
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Iftikhar A, Hassan H, Iftikhar N, Mushtaq A, Sohail A, Rosko N, Chakraborty R, Razzaq F, Sandeep S, Valent JN, Kanate AS, Anwer F. Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development. Antibodies (Basel) 2019; 8:E34. [PMID: 31544840 PMCID: PMC6640719 DOI: 10.3390/antib8020034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 05/12/2019] [Accepted: 05/13/2019] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. CONCLUSIONS Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.
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Affiliation(s)
- Ahmad Iftikhar
- Department of Internal Medicine, The University of Arizona, Tucson, AZ 85721, USA.
| | - Hamza Hassan
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA.
| | - Nimra Iftikhar
- Dow University of Health Sciences, Karachi 74200, Pakistan.
| | - Adeela Mushtaq
- Department of Internal Medicine, University of Pittsburgh Medical Center, McKeesport, PA 16148, USA.
| | - Atif Sohail
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA.
| | - Nathaniel Rosko
- Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44106, USA.
| | | | - Faryal Razzaq
- Foundation University Medical College, Islamabad 44000, Pakistan.
| | - Sonia Sandeep
- Department of Pathology, Wilson Medical Center, Wilson, NC 27893, USA.
| | | | | | - Faiz Anwer
- Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44106, USA.
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13
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Sohail A, Mushtaq A, Iftikhar A, Warraich Z, Kurtin SE, Tenneti P, McBride A, Anwer F. Emerging immune targets for the treatment of multiple myeloma. Immunotherapy 2019; 10:265-282. [PMID: 29421983 DOI: 10.2217/imt-2017-0136] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising.
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Affiliation(s)
- Atif Sohail
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Adeela Mushtaq
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Ahmad Iftikhar
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Zabih Warraich
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Sandra E Kurtin
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Pavan Tenneti
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
| | - Ali McBride
- College of Pharmacy, The University of Arizona, Tucson, AZ 85719, USA
| | - Faiz Anwer
- Department of Medicine, Division of Hematology/Oncology, The University of Arizona, Tucson, AZ 85724, USA
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14
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Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target? Neoplasia 2018; 21:93-105. [PMID: 30529074 PMCID: PMC6282459 DOI: 10.1016/j.neo.2018.10.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/30/2018] [Accepted: 10/31/2018] [Indexed: 11/22/2022] Open
Abstract
Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.
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15
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Zarfati M, Avivi I, Brenner B, Katz T, Aharon A. Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis. Angiogenesis 2018; 22:185-196. [PMID: 30386953 DOI: 10.1007/s10456-018-9649-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
Abstract
Bone marrow microenvironment is known to support angiogenesis, thus contributing to progression of multiple myeloma (MM). Bortezomib, a proteasome inhibitor (PI) widely used in MM treatment, has anti-angiogenic activity. Extracellular vesicles (EVs), shedding from cell surface, serve as mediators in cell-to-cell communication. We have hypothesized that MM cells (MMCs) treated with bortezomib generate EVs that could diminish angiogenesis, thus limiting MM progression. In the present study, EVs were obtained from MMCs (RPMI-8226), untreated (naïve) or pre-treated with bortezomib. EVs were outlined using NanoSight, FACS, protein arrays and proteasome activity assays. The impact of MMC-EVs on endothelial cell (EC) functions was assessed, employing XTT assay, Boyden chamber and Western blot. A high apoptosis level (annexin V binding 70.25 ± 16.37%) was observed in MMCs following exposure to bortezomib. Compared to naïve EVs, a large proportion of bortezomib-induced EVs (Bi-EVs) were bigger in size (> 300 nm), with higher levels of annexin V binding (p = 0.0043).They also differed in content, presenting with increased levels of pro-inflammatory proteins, reduced levels of pro-angiogenic growth factors (VEGFA, PDGF-BB, angiogenin), and displayed lower proteasome activity. Naïve EVs were found to promote EC migration and proliferation via ERK1/2 and JNK1/2/3 phosphorylation, whereas Bi-EVs inhibited these functions. Moreover, Bi-EVs appeared to reduce EC proteasome activity. EVs released from apoptotic MMCs following treatment with bortezomib can promote angiogenesis suppression by decreasing proliferation and migration of EC. These activities are found to be mediated by specific signal transduction pathways.
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Affiliation(s)
- Moran Zarfati
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - Irit Avivi
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Benjamin Brenner
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Tami Katz
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Anat Aharon
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. .,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel.
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16
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Lamanuzzi A, Saltarella I, Desantis V, Frassanito MA, Leone P, Racanelli V, Nico B, Ribatti D, Ditonno P, Prete M, Solimando AG, Dammacco F, Vacca A, Ria R. Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma. Oncotarget 2018; 9:20563-20577. [PMID: 29755672 PMCID: PMC5945497 DOI: 10.18632/oncotarget.25003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 03/13/2018] [Indexed: 01/27/2023] Open
Abstract
The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Matrigel®, and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic Membrane (CAM) and Matrigel® plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients.
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Affiliation(s)
- Aurelia Lamanuzzi
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Maria Antonia Frassanito
- Department of Biomedical Sciences and Human Oncology, General Pathology Unit, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Beatrice Nico
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro Medical School, Bari, Italy.,National Cancer Institute Giovanni Paolo II, Bari, Italy
| | | | - Marcella Prete
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Francesco Dammacco
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Roberto Ria
- Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy
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17
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Rao L, De Veirman K, Giannico D, Saltarella I, Desantis V, Frassanito MA, Solimando AG, Ribatti D, Prete M, Harstrick A, Fiedler U, De Raeve H, Racanelli V, Vanderkerken K, Vacca A. Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin ® protein MP0250: a preclinical study. Oncotarget 2018; 9:13366-13381. [PMID: 29568363 PMCID: PMC5862584 DOI: 10.18632/oncotarget.24351] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 01/25/2018] [Indexed: 01/10/2023] Open
Abstract
The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients.
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Affiliation(s)
- Luigia Rao
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Kim De Veirman
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Donato Giannico
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Maria Antonia Frassanito
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | - Marcella Prete
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | | | | | - Hendrik De Raeve
- Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Karin Vanderkerken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
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18
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Zagouri F, Terpos E, Kastritis E, Dimopoulos MA. Emerging antibodies for the treatment of multiple myeloma. Expert Opin Emerg Drugs 2016; 21:225-37. [DOI: 10.1080/14728214.2016.1186644] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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19
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Glavey SV, Manier S, Sacco A, Salem K, Kawano Y, Bouyssou J, Ghobrial IM, Roccaro AM. Epigenetics in Multiple Myeloma. Cancer Treat Res 2016; 169:35-49. [PMID: 27696257 DOI: 10.1007/978-3-319-40320-5_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Multiple myeloma is characterized by clonal proliferation of plasma cells within the bone marrow resulting in anemia, lytic bone lesions, hypercalcemia, and renal impairment. Despite advanced in our understanding of this complex disease in recent years, it is still considered an incurable malignancy. This is, in part, due to the highly heterogenous genomic and phenotypic nature of the disease, which is to date incompletely understood. It is clear that a deeper level of knowledge of the biological events underlying the development of these diseases is needed to identify new targets and generate effective novel therapies. MicroRNAs (miRNAs), which are single strand, 20-nucleotide, noncoding RNA's, are key regulators of gene expression and have been reported to exert transcriptional control in multiple myeloma. miRNAs are now recognized to play a role in many key areas such as cellular proliferation, differentiation, apoptosis and stress response. Substantial advances have been made in recent years in terms of our understanding of the biological role of miRNAs in a diverse range of hematological and solid malignancues, In multiple myeloma these advances have yielded new information of prognostic and diagnostic relevance which have helped to shed light on epigenetic regulation in this disease.
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Affiliation(s)
- Siobhan V Glavey
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Salomon Manier
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Antonio Sacco
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Karma Salem
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yawara Kawano
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Juliette Bouyssou
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Irene M Ghobrial
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Aldo M Roccaro
- Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA. .,Department of Hematology, CREA Laboratory, ASST-Spedali Civili di Brescia, Brescia, BS, Italy.
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Magarotto V, Salvini M, Bonello F, Bringhen S, Palumbo A. Strategy for the treatment of multiple myeloma utilizing monoclonal antibodies: A new era begins. Leuk Lymphoma 2015; 57:537-56. [DOI: 10.3109/10428194.2015.1102245] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Valeria Magarotto
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Marco Salvini
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Francesca Bonello
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Sara Bringhen
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Antonio Palumbo
- Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
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Ferrucci A, Moschetta M, Frassanito MA, Berardi S, Catacchio I, Ria R, Racanelli V, Caivano A, Solimando AG, Vergara D, Maffia M, Latorre D, Rizzello A, Zito A, Ditonno P, Maiorano E, Ribatti D, Vacca A. A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target. Clin Cancer Res 2014; 20:5796-807. [PMID: 25212607 DOI: 10.1158/1078-0432.ccr-14-0847] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group). EXPERIMENTAL DESIGN The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo. RESULTS Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo. CONCLUSIONS An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma.
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Affiliation(s)
- Arianna Ferrucci
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Michele Moschetta
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Maria Antonia Frassanito
- General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Simona Berardi
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Ivana Catacchio
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Roberto Ria
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Antonella Caivano
- Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Rionero in Vulture, Italy
| | - Antonio Giovanni Solimando
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Daniele Vergara
- Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Michele Maffia
- Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Dominga Latorre
- Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Antonia Rizzello
- Laboratory of General Physiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Alfredo Zito
- Pathological Anatomy Unit, Di Venere Hospital, Bari, Italy
| | | | - Eugenio Maiorano
- Pathological Anatomy Unit, University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, and National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | - Angelo Vacca
- Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
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Donato F, Gay F, Bringhen S, Troia R, Palumbo A. Monoclonal antibodies currently in Phase II and III trials for multiple myeloma. Expert Opin Biol Ther 2014; 14:1127-44. [DOI: 10.1517/14712598.2014.908848] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Yan H, Wu QL, Sun CY, Ai LS, Deng J, Zhang L, Chen L, Chu ZB, Tang B, Wang K, Wu XF, Xu J, Hu Y. piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma. Leukemia 2014; 29:196-206. [PMID: 24732595 DOI: 10.1038/leu.2014.135] [Citation(s) in RCA: 169] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 03/05/2014] [Accepted: 04/09/2014] [Indexed: 12/17/2022]
Abstract
Aberrant DNA hypermethylation contributes to myelomagenesis by silencing tumor-suppressor genes. Recently, a few reports have suggested that a novel class of small non-coding RNAs, called Piwi-interacting RNAs (piRNAs), may be involved in the epigenetic regulation of cancer. In this study, for the first time we provided evidence that the expression of piRNA-823 was upregulated in multiple myeloma (MM) patients and cell lines, and positively correlated with clinical stage. Silencing piRNA-823 in MM cells induced deregulation of cell cycle regulators and apoptosis-related proteins expression, accompanied by inhibition of tumorigenicity in vitro and in vivo. Moreover, piRNA-823 was directly relevant to de novo DNA methyltransferases, DNMT3A and 3B, in primary CD138(+) MM cells. The inhibited expression of piRNA-823 in MM cells resulted in marked reduction of DNMT3A and 3B at both mRNA and protein levels, which in turn led to decrease in global DNA methylation and reexpression of methylation-silenced tumor suppressor, p16(INK4A). In addition, piRNA-823 abrogation in MM cells induced reduction of vascular endothelial growth factor secretion, with consequent decreased proangiogenic activity. Altogether, these data support an oncogenic role of piRNA-823 in the biology of MM, providing a rational for the development of piRNA-targeted therapeutic strategies in MM.
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Affiliation(s)
- H Yan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Q-L Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - C-Y Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - L-S Ai
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - J Deng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - L Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - L Chen
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Z-B Chu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - B Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - K Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - X-F Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - J Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Y Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ria R, Catacchio I, Berardi S, De Luisi A, Caivano A, Piccoli C, Ruggieri V, Frassanito MA, Ribatti D, Nico B, Annese T, Ruggieri S, Guarini A, Minoia C, Ditonno P, Angelucci E, Derudas D, Moschetta M, Dammacco F, Vacca A. HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target. Clin Cancer Res 2013; 20:847-58. [PMID: 24297864 DOI: 10.1158/1078-0432.ccr-13-1950] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. EXPERIMENTAL DESIGN HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed. RESULTS Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival. CONCLUSIONS The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.
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Affiliation(s)
- Roberto Ria
- Authors' Affiliations: Section of Internal Medicine, Department of Biomedical Sciences and Human Oncology; Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy; Department of Human Anatomy, Histology and Embryology, and Pathological Anatomy, University of Bari Medical School; Hematology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Oncologic Hospital; Laboratory of Preclinical and Translational Research, IRCCS Basilicata Cancer Reference Centre, Potenza; Department of Clinical and Experimental Medicine, University of Foggia Medical School, Foggia; Hematology Unit, Ospedale Di Venere, Carbonara di Bari, Bari; and Department of Haematology, Businco Hospital, Cagliari, Italy
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Danylesko I, Beider K, Shimoni A, Nagler A. Monoclonal antibody-based immunotherapy for multiple myeloma. Immunotherapy 2013; 4:919-38. [PMID: 23046236 DOI: 10.2217/imt.12.82] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Multiple myeloma (MM) is a life-threatening hematological malignancy. High-dose chemotherapy followed by autologous stem cell transplantation is a relatively effective treatment, but disease recurrence remains a major obstacle. Allogeneic transplantation may result in durable responses and cure due to antitumor immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. This review will focus on MM antigens and their specific antibodies. These monoclonal antibodies are an attractive therapeutic tool for MM humoral immunotherapy, with most promising preclinical results.
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Affiliation(s)
- Ivetta Danylesko
- Division of Hematology, Bone Marrow Transplantation & Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer & Tel Aviv University, Tel Aviv, Israel
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Sionov RV. MicroRNAs and Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies. ISRN HEMATOLOGY 2013; 2013:348212. [PMID: 23431463 PMCID: PMC3569899 DOI: 10.1155/2013/348212] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Accepted: 11/14/2012] [Indexed: 12/20/2022]
Abstract
The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The journey through the multifaceted complexity of GC-induced apoptosis brings forth explanations for the differential treatment response and raises potential strategies for overcoming drug resistance.
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Affiliation(s)
- Ronit Vogt Sionov
- The Department of Biochemistry and Molecular Biology, The Institute for Medical Research-Israel-Canada, Hadassah Medical School, The Hebrew University of Jerusalem, Ein-Kerem, 91120 Jerusalem, Israel
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Balakrishnan K, Majesky M, Perkins JA. Head and neck lymphatic tumors and bony abnormalities: a clinical and molecular review. Lymphat Res Biol 2012; 9:205-12. [PMID: 22196287 DOI: 10.1089/lrb.2011.0018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Lymphatic malformations and lymphatic-derived tumors commonly involve the head and neck, where they may be associated with bony abnormalities and other systemic symptoms. The reasons for the association between these disorders and local skeletal changes are largely unknown, but such changes may cause significant disease-related morbidity. Ongoing work in molecular and developmental biology is beginning to uncover potential reasons for the bony abnormalities found in head and neck lymphatic disease; this article summarizes current knowledge on possible mechanisms underlying this association.
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Affiliation(s)
- Karthik Balakrishnan
- University of Washington, Department of Otolaryngology/Head and Neck Surgery, Seattle, WA, USA
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Azab F, Azab AK, Maiso P, Calimeri T, Flores L, Liu Y, Quang P, Roccaro AM, Sacco A, Ngo HT, Zhang Y, Morgan BL, Carrasco RD, Ghobrial IM. Eph-B2/ephrin-B2 interaction plays a major role in the adhesion and proliferation of Waldenstrom's macroglobulinemia. Clin Cancer Res 2012; 18:91-104. [PMID: 22010211 DOI: 10.1158/1078-0432.ccr-11-0111] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The ephrin receptors (Eph) are found in a wide range of cancers and correlate with metastasis. In this study, we characterized the role of Eph-B2 receptor in the interaction of Waldenstrom's macroglobulinemia (WM) cells with the bone marrow microenvironment. EXPERIMENTAL DESIGN We screened the activity of different receptor tyrosine kinases in WM patients and found that Eph-B2 was overexpressed compared with control. Also, we tested the expression of ephrin-B2 ligand on endothelial cells and bone marrow stromal cells (BMSC) isolated from WM patients. We then tested the role of Eph-B2/Ephrin-B2 interaction in the adhesion of WM cells to endothelial cells and BMSCs; the cell signaling induced by the coculture in both the WM cells and the endothelial cells; WM cell proliferation, apoptosis, and cell cycle in vitro and tumor progression in vivo; and in angiogenesis. RESULTS Eph-B2 receptor was found to be activated in WM patients compared with control, with a 5-fold increase in CD19(+) WM cells, and activated cell adhesion signaling, including focal adhesion kinase, Src, P130, paxillin, and cofilin, but decreased WM cell chemotaxis. Ephrin-B2 ligand was highly expressed on endothelial cells and BMSCs isolated from WM patients and on human umbilical vein endothelial cells and induced signaling in the endothelial cells promoting adhesion and angiogenesis. Blocking of ephrin-B2 or Eph-B2 inhibited adhesion, cytoskeletal signaling, proliferation, and cell cycle in WM cells, which was induced by coculture with endothelial cells and decreased WM tumor progression in vivo. CONCLUSION Ephrin-B2/Eph-B2 axis regulates adhesion, proliferation, cell cycle, and tumor progression in vivo through the interaction of WM with the cells in the bone marrow microenvironment.
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Affiliation(s)
- Feda Azab
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Abstract
The introduction of autologous stem cell transplantation combined with the introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors has significantly improved survival of multiple myeloma patients. However, ultimately the majority of patients will develop refractory disease, indicating the need for new treatment modalities. In preclinical and clinical studies, promising results have been obtained with several monoclonal antibodies (mAbs) targeting the myeloma tumor cell or the bone marrow microenvironment. The mechanisms underlying the therapeutic efficacy of these mAbs include direct induction of tumor cell apoptosis via inhibition or activation of target molecules, complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC). The capability of IMiDs to enhance ADCC and the modulation of various important signaling cascades in myeloma cells by both bortezomib and IMiDs forms the rationale to combine these novel agents with mAbs as new treatment strategies for myeloma patients. In this review, we will give an overview of various mAbs directly targeting myeloma tumor cells or indirectly via effects on the bone marrow microenvironment. Special focus will be on the combination of these mAbs with IMiDs or bortezomib.
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De Luisi A, Ferrucci A, Coluccia AML, Ria R, Moschetta M, de Luca E, Pieroni L, Maffia M, Urbani A, Di Pietro G, Guarini A, Ranieri G, Ditonno P, Berardi S, Caivano A, Basile A, Cascavilla N, Capalbo S, Quarta G, Dammacco F, Ribatti D, Vacca A. Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Res 2011; 17:1935-46. [PMID: 21307145 DOI: 10.1158/1078-0432.ccr-10-2381] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a "lead compound" of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC). EXPERIMENTAL DESIGN The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, "wound" healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels. RESULTS Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 μmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways. CONCLUSIONS This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM.
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Affiliation(s)
- Annunziata De Luisi
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
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Guan YS, He Q. Sorafenib: activity and clinical application in patients with hepatocellular carcinoma. Expert Opin Pharmacother 2011; 12:303-13. [DOI: 10.1517/14656566.2011.546346] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Evidence of a role for the novel zinc-finger transcription factor ZKSCAN3 in modulating Cyclin D2 expression in multiple myeloma. Oncogene 2010; 30:1329-40. [PMID: 21057542 DOI: 10.1038/onc.2010.515] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dysregulation of cyclin D2 contributes to the pathogenesis of multiple myeloma, and can occur through translocations that activate MAF/MAFB or MMSET/FGFR3. However, cyclin D2 induction can also be seen in the absence of such translocations, such as in patients with hyperdiploid disease, through unknown mechanisms. In UniGene cluster data-mining and ECgene analysis, we found that zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel transcription factor, is overrepresented in this malignancy, and three consensus ZKSCAN3 binding sites were found in the cyclin D2 promoter. Analysis of a panel of myeloma cell lines, primary patient samples and datasets from Oncomine and the Multiple Myeloma Genomics Portal (MMGP) revealed expression of ZKSCAN3 messenger RNA (mRNA) in a majority of samples. Studies of cell lines by western blotting, and of primary tissue microarrays by immunohistochemistry, showed ZKSCAN3 protein expression in a majority, and in a manner that paralleled messenger levels in cell lines. ZKSCAN3 overexpression was associated with increased gene copy number or genomic DNA gain/amplification in a subset based on analysis of data from the MMGP, and from fluorescence in situ hybridization studies of cell lines and primary samples. Overexpression of ZKSCAN3 induced cyclin D2 promoter activity in a MAF/MAFB-independent manner, and to an extent that was influenced by the number of consensus ZKSCAN3 binding sites. Moreover, ZKSCAN3 protein expression correlated with cyclin D2 levels in cell lines and primary samples, and its overexpression induced cyclin D2. Conversely, ZKSCAN3 suppression using small hairpin RNAs (shRNAs) reduced cyclin D2 levels, and, importantly, inhibited myeloma cell line proliferation. Finally, ZKSCAN3 was noted to specifically bind to oligonucleotides representing sequences from the cyclin D2 promoter, and to the endogenous promoter itself in myeloma cells. Taken together, the data support the conclusion that ZKSCAN3 induction represents a mechanism by which myeloma cells can induce cyclin D2 dysregulation, and contribute to disease pathogenesis.
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Shi Q, Nguyen AT, Angell Y, Deng D, Na CR, Burgess K, Roberts DD, Brunicardi FC, Templeton NS. A combinatorial approach for targeted delivery using small molecules and reversible masking to bypass nonspecific uptake in vivo. Gene Ther 2010; 17:1085-97. [PMID: 20463761 PMCID: PMC2923228 DOI: 10.1038/gt.2010.55] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Revised: 02/03/2010] [Accepted: 02/18/2010] [Indexed: 12/21/2022]
Abstract
We have developed a multi-disciplinary approach combining molecular biology, delivery technology, combinatorial chemistry and reversible masking to create improved systemic, targeted delivery of plasmid DNA while avoiding nonspecific uptake in vivo. We initially used a well-characterized model targeting the asialolglycoprotein receptor in the liver. Using our bilamellar invaginated vesicle (BIV) liposomal delivery system with reversible masking, we increased expression in the liver by 76-fold, nearly equaling expression in first-pass organs using non-targeted complexes, with no expression in other organs. The same technology was then applied to efficiently target delivery to a human tumor microenvironment model. We achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass nonspecific tissues and organs. We identified ligands that target a human tumor microenvironment created in vitro by co-culturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and vascular endothelial growth factor-A, and prolonged survival of endothelial capillary-like structures. The co-cultures were used for high-throughput screening of a specialized small molecule library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules that enhanced the transfection efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. Intravenous (i.v.) injection of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment approximately 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five i.v. injections administered once every week.
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Affiliation(s)
- Qiaoyun Shi
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
| | - Andrew T. Nguyen
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
| | - Yu Angell
- Department of Chemistry, Box 30012, Texas A&M University, College Station, Texas 77841
| | - Defeng Deng
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
| | - Chang-Rim Na
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
| | - Kevin Burgess
- Department of Chemistry, Box 30012, Texas A&M University, College Station, Texas 77841
| | - David D. Roberts
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - F. Charles Brunicardi
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
| | - Nancy Smyth Templeton
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
- Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030
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Biological impact of vascular endothelial growth factor on vessel density and survival in multiple myeloma and plasmacytoma. Pathol Res Pract 2010; 206:753-9. [PMID: 20709463 DOI: 10.1016/j.prp.2010.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Accepted: 07/02/2010] [Indexed: 12/25/2022]
Abstract
We compared the differences in a number of angiogenesis-related immunohistochemical parameters, including microvascular density (MVD) and tumor cell activity, between multiple myeloma (MM) and solitary plasmacytoma (SP). Tissue sections from tumors of MM and SP were immunohistochemically stained and analyzed using ImageJ image analysis software for the expression of vascular endothelial growth factor (VEGF), VEGF receptors (Flt-1 and Flk-1), inducible nitric oxide (iNOS), and anti-apoptotic (Bcl-2) protein. Tumor tissues were cytologically graded as high-, intermediate-, or low-grade. Two pathologists determined the MVD of each section independently by recording the average number of CD34+ blood vessels in 500 unit fields. The arithmetic means for MVD were statistically analyzed using the Student's t-test and the significance level was calculated at P-value <0.001. The results indicate a direct correlation between upregulation of iNOS/VEGF in high-grade tumors. For MM, an increase in MVD is also correlated with a high-grade. Tumor survival signaling by Bcl-2 in both SP and MM emphasizes the fact that VEGF has a bimodal role that is mainly angiogenic in MM and tumorigenic, promoting tumor cell survival in SP.
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Abstract
Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138(+) MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-kappaB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.
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Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood 2008; 112:1346-56. [PMID: 18524994 DOI: 10.1182/blood-2007-10-116590] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRbeta) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRbeta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRbeta/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRbeta/c-Src TKs in MM, providing a framework for future clinical trials.
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Addition of PTK787/ZK 222584 can lower the dosage of amsacrine to achieve equal amounts of acute myeloid leukemia cell death. Anticancer Drugs 2008; 19:45-54. [PMID: 18043129 DOI: 10.1097/cad.0b013e3282f1be0b] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Acute myeloid leukemia (AML) is a disease with a poor prognosis. It has been demonstrated that AML cells express the vascular endothelial growth factors, VEGFA and VEGFC, as well as kinase insert domain-containing receptor (VEGFR2), the main receptor for downstream effects, resulting in an autocrine pathway for cell survival. This study investigates the role of the VEGFR inhibitor PTK787/ZK 222584 in leukemic cell death, and the possibility of an additional effect on cell death by a chemotherapeutic drug, amsacrine. In three AML cell lines and 33 pediatric AML patient samples, we performed total cell-kill assays to determine the percentages of cell death achieved by PTK787/ZK 222584 and/or amsacrine. Both drugs induced AML cell death. Using a response surface analysis, we could show that, in cell lines as well as in primary AML blasts, an equal magnitude of leukemic cell death could be obtained when lower doses of the more toxic amsacrine were combined with low dosages of the less toxic VEGFR inhibitor. This study shows that PTK787/ZK 222584 might have more clinical potential in AML when combined with a chemotherapeutic drug such as amsacrine. In future, it will be interesting to study whether the complications and the long-term effects of chemotherapy can be reduced by lowering the dosages of amsacrine, and by replacing it with other drugs with lower toxicity profiles, such as PTK787/ZK 222584.
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Scavelli C, Di Pietro G, Cirulli T, Coluccia M, Boccarelli A, Giannini T, Mangialardi G, Bertieri R, Coluccia AML, Ribatti D, Dammacco F, Vacca A. Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther 2007; 6:3256-62. [PMID: 18089719 DOI: 10.1158/1535-7163.mct-07-0311] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma.
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Affiliation(s)
- Claudio Scavelli
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare, 11, I-70124 Bari, Italy
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Drescher D, Moehler M, Gockel I, Frerichs K, Müller A, Dünschede F, Borschitz T, Biesterfeld S, Holtmann M, Wehler T, Teufel A, Herzer K, Fischer T, Berger MR, Junginger T, Galle PR, Schimanski CC. Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma-a rationale for a molecular targeting strategy? World J Gastroenterol 2007; 13:3605-9. [PMID: 17659711 PMCID: PMC4146800 DOI: 10.3748/wjg.v13.i26.3605] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma.
METHODS: The (co-)expression pattern of VEGFR1-3, PDGFRα/β and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation.
RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFRα (82%) and PDGFRβ (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRα revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFRβ was restricted to stromal pericytes, which also depicted a PDGFRα expression.
CONCLUSION: Our results reveal a high rate of receptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy.
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Affiliation(s)
- Daniel Drescher
- Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Mainz, Germany
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Anagnostopoulos A, Eleftherakis-Papaiakovou V, Kastritis E, Tsionos K, Bamias A, Meletis J, Dimopoulos MA, Terpos E. Serum concentrations of angiogenic cytokines in Waldenstrom macroglobulinaemia: the ratio of angiopoietin-1 to angiopoietin-2 and angiogenin correlate with disease severity. Br J Haematol 2007; 137:560-8. [PMID: 17451406 DOI: 10.1111/j.1365-2141.2007.06609.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Angiogenesis represents an essential step of disease progression in several haematological malignancies. Microvessel density is increased in 30% of patients with Waldenstrom macroglobulinaemia (WM), but there is very limited information regarding the role of angiogenic cytokines in this disease. Serum levels of vascular endothelial growth factor (VEGF), VEGF-A, angiogenin, angiopoietin (Ang)-1 and -2, and basic fibroblast growth factor (bFGF) were evaluated in 56 WM patients at different disease phases (24 untreated, 20 relapsed/refractory and 12 patients at remission) and 11 patients with immunoglobulin M type monoclonal gammopathy of undetermined significance (IgM-MGUS). All patients had increased levels of angiogenin, VEGF, VEGF-A, and bFGF compared with controls. The Ang-1/Ang-2 ratio was reduced in WM but not in IgM-MGUS patients. Angiogenin levels correlated with disease status: when compared with healthy subjects, patients with IgM-MGUS and untreated WM patients had increased angiogenin serum levels, which were higher in untreated WM patients than in MGUS. WM patients at remission had lower angiogenin serum levels compared with untreated patients, but these levels were increased again in active disease post-therapy. Angiogenin also correlated with albumin levels, while VEGF-A correlated with beta(2)-microglobulin (beta2M). Ang-1/Ang-2 ratio showed a strong, negative correlation with beta2M, and positive correlation with albumin, haemoglobin and lymphadenopathy. Our results indicate a potential use of angiogenin levels for follow-up in WM and angiogenic molecules as targets for the development of novel anti-WM agents.
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Affiliation(s)
- Athanasios Anagnostopoulos
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
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Dong X, Han ZC, Yang R. Angiogenesis and antiangiogenic therapy in hematologic malignancies. Crit Rev Oncol Hematol 2006; 62:105-18. [PMID: 17188504 DOI: 10.1016/j.critrevonc.2006.11.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2006] [Revised: 11/13/2006] [Accepted: 11/15/2006] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.
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Affiliation(s)
- Xunwei Dong
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China
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Alexandrakis MG, Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A, Stathopoulos EN. Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma. Eur J Intern Med 2006; 17:412-6. [PMID: 16962948 DOI: 10.1016/j.ejim.2006.02.012] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2005] [Revised: 01/12/2006] [Accepted: 02/20/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND Interleukin-17 (IL-17) is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial cell growth factor (VEGF). Angiogenesis is implicated in the progression of multiple myeloma (MM). METHODS We measured serum levels of IL-17, TNF-alpha, and VEGF, as well as microvessel density (MVD) in 40 untreated MM patients. RESULTS Levels of IL-17 in the sera of patients with MM were higher than those in matched controls; however, the difference did not reach statistical significance. Serum levels of both TNF-alpha and VEGF in MM patients were significantly higher than those in controls (p<0.001 in both instances). Levels of IL-17 in MM patients, both stage II and stage III, were significantly higher than those of stage I patients (p=0.001 and p<0.001, respectively). Similarly, higher values of VEGF (p<0.001), TNF-alpha (p<0.001), and MVD (p<0.035) were associated with advanced disease stage. Serum values of IL-17 in MM patients correlated positively not only with VEGF (Spearman's rho=0.606) and TNF-alpha (r=0.552; p<0.001 in both instances), but also with MVD (r=0.385, p=0.014). In addition, a positive correlation was found between serum values of VEGF and TNF-alpha (r=0.657, p<0.001), MVD and VEGF (r=0.353, p=0.026), and between MVD and TNF-alpha (r=0.506, p=0.001) in MM patients. CONCLUSION These results suggest that IL-17 plays a role in the promotion of angiogenesis and associated disease progression in MM.
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Affiliation(s)
- Michael G Alexandrakis
- Department of Haematology, University Hospital of Heraklion, P.O. Box 1352, Heraklion, Crete, Greece
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Vacca A, Scavelli C, Serini G, Di Pietro G, Cirulli T, Merchionne F, Ribatti D, Bussolino F, Guidolin D, Piaggio G, Bacigalupo A, Dammacco F. Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 2006; 108:1661-7. [PMID: 16684957 DOI: 10.1182/blood-2006-04-014563] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Vascular endothelial growth factor165 (VEGF165) and semaphorin3A (SEMA3A) elicit pro- and antiangiogenic signals respectively in endothelial cells (ECs) by binding to their receptors VEGFR-2, neuropilin-1 (NRP1), and plexin-A1. Here we show that the VEGF165-driven angiogenic potential of multiple myeloma (MM) ECs is significantly higher than that of monoclonal gammopathy of undetermined significance (MGUS) ECs (MGECs) and human umbilical vein (HUV) ECs. This is probably due to a constitutive imbalance of endogenous VEGF165/SEMA3A ratio, which leans on VEGF165 in MMECs but on SEMA3A in MGECs and HUVECs. Exogenous VEGF165 induces SEMA3A expression in MGECs and HUVECs, but not in MMECs. Moreover, by counteracting VEGF165 activity as efficiently as an anti-VEGFR-2 antibody, exogenous SEMA3A restrains the over-angiogenic potential of MMECs. Our data indicate that loss of endothelial SEMA3A in favor of VEGF165 could be responsible for the angiogenic switch from MGUS to MM.
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Affiliation(s)
- Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
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Abstract
Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and has prognostic potential. It is induced by plasma cells via angiogenic factors with the transition from monoclonal gammopathy of undetermined significance (MGUS) to MM, and probably with loss of angiostatic activity on the part of MGUS. The pathophysiology of MM-induced angiogenesis is complex and involves both direct production of angiogenic cytokines by plasma cells and their induction within the microenvironment. The latter are secreted by stromal cells, endothelial cells (EC) and osteoclasts, and promote plasma cell growth, survival and migration, as well as paracrine cytokine secretion and angiogenesis in the bone marrow milieu. Angiogenesis is also supported by inflammatory cells following their recruitment and activation by plasma cells. Finally, circulating EC and endothelial precursor cells (EPC) contribute to the neovascularization, and the presence of EPC suggests that vasculogenesis (new vessel formation from EPC) may also contribute to the full MM vascular tree.
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Affiliation(s)
- A Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
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Ribatti D, Nico B, Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 2006; 25:4257-66. [PMID: 16518413 DOI: 10.1038/sj.onc.1209456] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.
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Affiliation(s)
- D Ribatti
- Department of Human Anatomy and Histology, University of Bari Medical School, Italy.
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Vacca A, Scavelli C, Montefusco V, Di Pietro G, Neri A, Mattioli M, Bicciato S, Nico B, Ribatti D, Dammacco F, Corradini P. Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma. J Clin Oncol 2005; 23:5334-46. [PMID: 15939924 DOI: 10.1200/jco.2005.03.723] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose To study the antiangiogenic effect of thalidomide. Patients and Methods The expression of key angiogenic genes was studied in bone marrow endothelial cells (ECs) of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies unattributed/unassociated (MG[u]), diffuse large B-cell non-Hodgkin's lymphoma, in a Kaposi's sarcoma (KS) cell line, and in healthy human umbilical vein ECs (HUVECs) following exposure to therapeutic doses of thalidomide. Results Thalidomide markedly downregulates the genes in a dose-dependent fashion in active MMECs and KS cell line, but upregulates them or is ineffective in nonactive MMECs, MG(u)ECs, NHL-ECs, and in HUVECs. Secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor also diminishes according to the dose in culture conditioned media (CM) of active MMECs and KS, whereas it does not change in the other CM. Conclusion Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Angiogenesis Inhibitors/pharmacology
- Bone Marrow/pathology
- Cells, Cultured
- Culture Media, Conditioned
- Down-Regulation
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Enzyme-Linked Immunosorbent Assay
- Female
- Fibroblast Growth Factor 2/genetics
- Fibroblast Growth Factor 2/metabolism
- Gene Expression Profiling
- Hepatocyte Growth Factor/genetics
- Hepatocyte Growth Factor/metabolism
- Humans
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/metabolism
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Male
- Middle Aged
- Multiple Myeloma/drug therapy
- Multiple Myeloma/genetics
- Multiple Myeloma/metabolism
- Paraproteinemias/drug therapy
- Paraproteinemias/genetics
- Paraproteinemias/metabolism
- RNA, Messenger/metabolism
- RNA, Neoplasm/metabolism
- Sarcoma, Kaposi/drug therapy
- Sarcoma, Kaposi/genetics
- Sarcoma, Kaposi/metabolism
- Thalidomide/pharmacology
- Umbilical Veins/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, Policlinico-Piazza Giulio Cesare, University of Medical School Bari, Italy.
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