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A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular,...

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Autores principales: De Vita, Alessandro, Vanni, Silvia, Miserocchi, Giacomo, Fausti, Valentina, Pieri, Federica, Spadazzi, Chiara, Cocchi, Claudia, Liverani, Chiara, Calabrese, Chiara, Casadei, Roberto, Recine, Federica, Gurrieri, Lorena, Bongiovanni, Alberto, Ibrahim, Toni, Mercatali, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962296/
https://www.ncbi.nlm.nih.gov/pubmed/35203581
http://dx.doi.org/10.3390/biomedicines10020372
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author De Vita, Alessandro
Vanni, Silvia
Miserocchi, Giacomo
Fausti, Valentina
Pieri, Federica
Spadazzi, Chiara
Cocchi, Claudia
Liverani, Chiara
Calabrese, Chiara
Casadei, Roberto
Recine, Federica
Gurrieri, Lorena
Bongiovanni, Alberto
Ibrahim, Toni
Mercatali, Laura
author_facet De Vita, Alessandro
Vanni, Silvia
Miserocchi, Giacomo
Fausti, Valentina
Pieri, Federica
Spadazzi, Chiara
Cocchi, Claudia
Liverani, Chiara
Calabrese, Chiara
Casadei, Roberto
Recine, Federica
Gurrieri, Lorena
Bongiovanni, Alberto
Ibrahim, Toni
Mercatali, Laura
author_sort De Vita, Alessandro
collection PubMed
description Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management.
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spelling pubmed-89622962022-03-30 A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences De Vita, Alessandro Vanni, Silvia Miserocchi, Giacomo Fausti, Valentina Pieri, Federica Spadazzi, Chiara Cocchi, Claudia Liverani, Chiara Calabrese, Chiara Casadei, Roberto Recine, Federica Gurrieri, Lorena Bongiovanni, Alberto Ibrahim, Toni Mercatali, Laura Biomedicines Article Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management. MDPI 2022-02-03 /pmc/articles/PMC8962296/ /pubmed/35203581 http://dx.doi.org/10.3390/biomedicines10020372 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
De Vita, Alessandro
Vanni, Silvia
Miserocchi, Giacomo
Fausti, Valentina
Pieri, Federica
Spadazzi, Chiara
Cocchi, Claudia
Liverani, Chiara
Calabrese, Chiara
Casadei, Roberto
Recine, Federica
Gurrieri, Lorena
Bongiovanni, Alberto
Ibrahim, Toni
Mercatali, Laura
A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title_full A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title_fullStr A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title_full_unstemmed A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title_short A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
title_sort rationale for the activity of bone target therapy and tyrosine kinase inhibitor combination in giant cell tumor of bone and desmoplastic fibroma: translational evidences
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962296/
https://www.ncbi.nlm.nih.gov/pubmed/35203581
http://dx.doi.org/10.3390/biomedicines10020372
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