Next Article in Journal
Cigarette Smoke Containing Acrolein Upregulates EGFR Signaling Contributing to Oral Tumorigenesis In Vitro and In Vivo
Next Article in Special Issue
Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation
Previous Article in Journal
Text Messaging in Cancer-Supportive Care: A Systematic Review
Previous Article in Special Issue
Giant Cell Tumor of Bone in Patients under 16 Years Old: A Single-Institution Case Series
Article

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling

1
First Department of Orthopedic Surgery, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 65691 Brno, Czech Republic
2
Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic
3
International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
4
Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 66263 Brno, Czech Republic
5
First Pathology Department, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 65691 Brno, Czech Republic
6
Department of Chemistry, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Winette T.A. van der Graaf
Cancers 2021, 13(14), 3543; https://doi.org/10.3390/cancers13143543
Received: 10 May 2021 / Revised: 30 June 2021 / Accepted: 14 July 2021 / Published: 15 July 2021
(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)
The purpose of this study was to analyze differential cell signaling in response to denosumab treatment to identify and subsequently inhibit molecular targets in the neoplastic stromal cell population, which poses a risk for tumor recurrence. Using phosphoprotein arrays, a distinct signaling profile was detected in GCTB tissues treated with denosumab, a specific RANKL antibody, which coincided with the RTK profile in derived cell lines. PDGFRβ was selected as a promising receptor target, and its inhibition by the small-molecule inhibitor sunitinib resulted in potent inhibition of cell proliferation in vitro. The addition of sunitinib to denosumab resulted in the disappearance of both multinuclear giant cells and neoplastic stromal cells, as reported here. Thus, sunitinib could become an effective addition to denosumab in the treatment of GCTB with activated PDGFRβ.
Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy. View Full-Text
Keywords: giant-cell tumor of bone; targeted treatment; sunitinib; PDGFR beta; denosumab; signaling giant-cell tumor of bone; targeted treatment; sunitinib; PDGFR beta; denosumab; signaling
Show Figures

Graphical abstract

MDPI and ACS Style

Mahdal, M.; Neradil, J.; Mudry, P.; Paukovcekova, S.; Staniczkova Zambo, I.; Urban, J.; Macsek, P.; Pazourek, L.; Tomas, T.; Veselska, R. New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling. Cancers 2021, 13, 3543. https://doi.org/10.3390/cancers13143543

AMA Style

Mahdal M, Neradil J, Mudry P, Paukovcekova S, Staniczkova Zambo I, Urban J, Macsek P, Pazourek L, Tomas T, Veselska R. New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling. Cancers. 2021; 13(14):3543. https://doi.org/10.3390/cancers13143543

Chicago/Turabian Style

Mahdal, Michal, Jakub Neradil, Peter Mudry, Silvia Paukovcekova, Iva Staniczkova Zambo, Jiri Urban, Peter Macsek, Lukas Pazourek, Tomas Tomas, and Renata Veselska. 2021. "New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling" Cancers 13, no. 14: 3543. https://doi.org/10.3390/cancers13143543

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop