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, 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.

[1]  A. De Vita,et al.  Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas , 2021, International journal of molecular sciences.

[2]  G. Hu,et al.  Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone , 2021, Cell Death & Disease.

[3]  B. Morland,et al.  Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. , 2021, The Lancet Oncology.

[4]  T. Kondo,et al.  Establishment and characterization of novel patient-derived cell lines from giant cell tumor of bone , 2021, Human Cell.

[5]  H. Sakale,et al.  Mammoth Giant Cell Tumor of the First Metacarpal: A Case Report and Management Trends , 2021, Cureus.

[6]  A. De Vita,et al.  The potential role of the extracellular matrix in the activity of trabectedin in UPS and L-sarcoma: evidences from a patient‐derived primary culture case series in tridimensional and zebrafish models , 2021, Journal of experimental & clinical cancer research : CR.

[7]  Dil V. Patel,et al.  Giant cell tumor of the thoracic spine causing acute paraplegia-a case report. , 2021, Journal of spine surgery.

[8]  A. De Vita,et al.  Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas , 2021, Cancer biology & medicine.

[9]  N. Ramírez,et al.  Giant cell tumor of bone at the proximal epiphysis of humerus in a skeletally immature patient: A case report , 2020, International journal of surgery case reports.

[10]  A. Puri,et al.  The current standing on the use of denosumab in giant cell tumour of the bone , 2020, Journal of orthopaedic surgery.

[11]  M. Bianchi,et al.  The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration , 2020, Frontiers in Immunology.

[12]  J. Yayan Denosumab for Effective Tumor Size Reduction in Patients With Giant Cell Tumors of the Bone: A Systematic Review and Meta-Analysis , 2019, Cancer control : journal of the Moffitt Cancer Center.

[13]  Zhonglin Hao,et al.  Lenvatinib in Management of Solid Tumors. , 2019, The oncologist.

[14]  H. Gelderblom,et al.  Challenges of denosumab in giant cell tumor of bone, and other giant cell-rich tumors of bone , 2019, Current opinion in oncology.

[15]  K. Horiuchi,et al.  Desmoplastic fibroma of bone arising in the cortex of the proximal femur. , 2021, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[16]  D. Campanacci,et al.  Denosumab treatment of inoperable or locally advanced giant cell tumor of bone - Multicenter analysis outside clinical trial. , 2018, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[17]  D. Amadori,et al.  Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma. , 2018, Journal of visualized experiments : JoVE.

[18]  Hailin Zhao,et al.  The role of osteopontin in the progression of solid organ tumour , 2018, Cell Death & Disease.

[19]  K. Nakano,et al.  Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas , 2018, International journal of molecular sciences.

[20]  D. Amadori,et al.  Tumor-Stroma Crosstalk in Bone Tissue: The Osteoclastogenic Potential of a Breast Cancer Cell Line in a Co-Culture System and the Role of EGFR Inhibition , 2017, International journal of molecular sciences.

[21]  G. Farfalli,et al.  Denosumab-treated giant cell tumor of bone. Its histologic spectrum and potential diagnostic pitfalls. , 2017, Human pathology.

[22]  R. Mohankumar,et al.  Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone. , 2016, European journal of cancer.

[23]  D. Cohen,et al.  Desmoplastic Fibroma of the Mandible: A Series of Three Cases and Review of Literature , 2015, Head and Neck Pathology.

[24]  D. Amadori,et al.  CSF-1 blockade impairs breast cancer osteoclastogenic potential in co-culture systems. , 2014, Bone.

[25]  R. Grimer,et al.  Desmoplastic fibroma of bone: A rare bone tumour , 2014, Journal of bone oncology.

[26]  H. Gelderblom,et al.  The clinical approach toward giant cell tumor of bone. , 2014, The oncologist.

[27]  Kang Z. Liu,et al.  Protein kinase C regulates FLT1 abundance and stimulates its cleavage in vascular endothelial cells with the release of a soluble PlGF/VEGF antagonist. , 2013, Experimental cell research.

[28]  David M. Thomas,et al.  Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. , 2013, The Lancet. Oncology.

[29]  P. Raab,et al.  Desmoplastic Fibroma: A Case Report with Three Years of Clinical and Radiographic Observation and Review of the Literature , 2013, The open orthopaedics journal.

[30]  H. Knowles,et al.  VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology , 2012, Laboratory Investigation.

[31]  J. Wanders,et al.  A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours , 2012, British Journal of Cancer.

[32]  David M. Thomas,et al.  Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. , 2010, The Lancet. Oncology.

[33]  C. Errani,et al.  Giant cell tumor of the extremity: A review of 349 cases from a single institution. , 2010, Cancer treatment reviews.

[34]  P. Kostenuik,et al.  Denosumab, a Fully Human Monoclonal Antibody to RANKL, Inhibits Bone Resorption and Increases BMD in Knock‐In Mice That Express Chimeric (Murine/Human) RANKL , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  M. Balke,et al.  Giant cell tumor of bone: treatment and outcome of 214 cases , 2008, Journal of Cancer Research and Clinical Oncology.

[36]  M. Agarwal,et al.  Giant Cell Tumor of Bone in Children and Adolescents , 2007, Journal of pediatric orthopedics.

[37]  H. Yoshida,et al.  Giant cell tumor of bone , 2004, Virchows Archiv A.

[38]  S. Kumta,et al.  Expression of VEGF and MMP-9 in giant cell tumor of bone and other osteolytic lesions. , 2003, Life sciences.

[39]  P. Julka,et al.  Radiotherapy for Desmoplastic Fibroma of Bone: A Case Report , 2003, Journal of orthopaedic surgery.

[40]  P. Picci,et al.  Prognostic relevance of C‐myc gene expression in giant‐cell tumor of bone , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[41]  M. Laniado,et al.  Desmoplastic fibroma of the bone: A report of two patients, review of the literature, and therapeutic implications , 1996, Cancer.

[42]  N. Sanfilippo,et al.  Desmoplastic fibroma: a role for radiotherapy? , 1995, Southern medical journal.

[43]  W. Sanger,et al.  Cytogenetic findings and biologic behavior of giant cell tumors of bone , 1990, Cancer.

[44]  W. Enneking A system of staging musculoskeletal neoplasms. , 1986, Clinical orthopaedics and related research.

[45]  W. Ober Tumors and Tumorous Conditions of the Bones and Joints , 1959, The Yale Journal of Biology and Medicine.

[46]  H. Jaffe Giant-cell tumour (osteoclastoma) of bone: its pathologic delimitation and the inherent clinical implications. , 1953, Annals of the Royal College of Surgeons of England.

[47]  Yon E.udolpii On Tumours , 1864, The British and Foreign Medico-Chirurgical Review.