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Biologics in Musculoskeletal Oncology
Targeted Therapies in Orthopedic Oncology
As we continue to learn more about the pathophysiology of bone and soft tissue neoplasms, we are presented with new molecular targets for treatment. No chapter on the use of biologics in musculoskeletal oncology would be complete without a discussion of the use of biologics to treat these tumors. Targeted therapies, which use normal biology to manipulate pathologic genes and proteins, are evolving as an alternative to traditional cytotoxic chemotherapy.
Denosumab Treatment of Giant Cell Tumor of Bone
Giant cell tumor of bone (GCTB) is characterized as a benign, yet locally aggressive, tumor that can result in significant osteolysis and destruction of bone. Previous research has demonstrated that the neoplastic cells responsible for GCTB have roots drawing from aberrant and incomplete differentiation of mesenchymal stem cells along the osteoblast lineage. The histology is characterized by layers of mononuclear cells with high Receptor activator of nuclear factor k-beta (RANK) ligand (RANKL) expression, RANK-positive mononuclear cells of myeloid lineage, and large osteoclast-like giant cells which also express RANK. Each of these histologic features of GCTB makes denosumab an ideal treatment strategy. Denosumab is a human monoclonal antibody that specifically binds to RANK ligand. This provides therapeutic benefit by targeting the two physiologic pathways responsible for the aggressive osteolytic process: (1) reducing the number of RANK-positive giant cells and (2) reducing the number of mononuclear stromal cells that overexpress RANKL, which some authors believe is the true neoplastic cell in GCTB.
Early clinically trials, although small in size, show promising results. One previous cohort study evaluating denosumab treatment for GCTB found no disease progression in 96% (163/169) patients with surgically unsalvageable disease treated only with denosumab. The same study also found that of 100 eligible patients planned for surgical intervention, 74% did not need to undergo surgery after treatment, and of those remaining, 62% underwent a significantly less morbid procedure.
Tyrosine Kinase Inhibitors for Sarcoma
Recent advances in oncologic research have identified angiogenesis as a common pathway, critical in the growth, invasion, and subsequent metastases of multiple tumor types. Multiple growth factors are implicated in both the normal physiologic as well as pathologic processes. The importance of Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) has been identified as these growth factors initiate a cascade of intracellular signaling that culminates in the stimulation of endothelial cell proliferation, migration, and inhibition of apoptosis. This signaling process occurs through binding the external component of a transmembrane receptor linked to an intercellular tyrosine kinase, which initiates the aforementioned cascade of cellular events.
In sarcomas the interaction between VEGF and its tyrosine kinase receptor has recently been shown to be critical in tumor progression. These growth factors have also demonstrated their utility as prognostic indicators, with higher serum levels of VEGF strongly correlated with the poorest differentiated soft tissue sarcomas, and specifically in leiomyosarcoma, higher levels are associated with worse prognosis and shorter survival. As a result of these findings, the VEGF tyrosine kinase receptors have emerged as a key target in the development of new anticancer agents within the “cancer cell”–specific therapies. Initial clinical studies evaluating the efficacy of pazopanib in the treatment of soft tissue sarcomas have encouraging early results. A recent phase III trial demonstrated a significant improvement in progression-free survival in patients receiving pazopanib compared with placebo, yet no difference in overall survival was detected in the study. In light of these findings, the FDA approved the use of pazopanib for treatment of patients with advanced soft tissue sarcomas who have previously received chemotherapy. Although these early medications are still in the infancy of their development, they serve to highlight the critical clinical significance of these proangiogenic tyrosine kinase receptors and their potential as therapeutic targets to impair and inhibit progression of tumor grown.
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