Oncology
At university we learnt about the difference between tumour parenchyma (neoplastic) cells and tumour stromal (non-neoplastic or supporting) cells. Clearly it appeared that scientists should target the parenchymal cells to kill the tumour. Well it seems as if there is a lot more to those supporting cells – especially in aggressive disorders such as myeloma, bone metastases and giant cell tumour (GCT).
GCT, for example, is characterised by giant cells, but the actual neoplastic cells are tiny spindle cells with immature osteoblastic characteristics. Confusingly, these are called stromal cells! They express RANK ligand (RANKL) which mediates recruitment of the large giant cells derived from a monocyte-macrophage-osteoclast lineage and which cause such local bony destruction. In this pathological environment, uncoupling of the pathological ‘osteoblastic–osteoclastic’ interaction can be a worthwhile biological aspiration.
The drug Denosumab is a human monoclonal antibody against RANKL. The fist trial of its use in GCT led by Melbourne oncologist David Thomas1 identified an 86% tumour response rate confirming its efficacy in a neoadjuvant setting and suggesting a potent role in assisting the orthopaedic surgeon in gaining local tumour control. In addition a close interconnection between stromal and giant cells was found; giant cells are dependent on RANKL, but RANKL expression by stromal cells is diminished after elimination of giant cells. Stromal cells were replaced by more normal osteoblastic cells producing osteoid. These observations demonstrate that normal coupling of bone formative and resorptive mechanisms can be made pathological by genetic mutation and that uncoupling can be beneficial - at least for a short treatment period.
Evaluation of Denosumab and other RANKL inhibiting drugs is ongoing, and close cooperation between surgeon and oncologist is necessary to identify patient who might currently benefit from this intervention.
Mr Daniel Porter, Senior Lecturer in Orthopaedic Surgery, University of Edinburgh, UK
Reference
1. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant- cell tumour of bone - an open label, phase 2 study. The Lancet Oncology 2010;11:275-280.
