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

Mahdal, Michal; Neradil, Jakub; Mudry, Peter; Paukovcekova, Silvia; Staniczkova Zambo, Iva; Urban, Jiri; Macsek, Peter; Pazourek, Lukas; Tomas, Tomas; Veselska, Renata

doi:10.3390/cancers13143543

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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,†

^2,3,4,†

^3,4,†,

²,

Iva Staniczkova Zambo

^3,5

⁶

^2,3,

¹,

and

^2,3,4,*

First Department of Orthopedic Surgery, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 65691 Brno, Czech Republic

Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic

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)

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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.

Abstract

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

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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

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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

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