Several types of cancer are frequently associated with the spreading of tumour cells to the skeleton, where they cause bone destruction by activating osteoclasts (the cells that remove bone). This can lead to major complications, including severe bone pain and fractures. Bisphosphonates are a class of drugs used to treat this bone destruction. They act by preventing osteoclast cells from destroying the bone. However, it has become clear in recent years that these drugs can have other effects besides preventing the bone destruction. In animal studies, these drugs have been shown to have anti-tumour effects against a variety of tumour types, including osteosarcoma. They decrease tumour burden, prevent tumour spreading, and increase survival of tumour-bearing mice and rats. However, the exact way in which bisphosphonate drugs affect tumours is not known. In particular, it is not known whether the drugs can directly affect cells other than osteoclasts in these animal models.

Identifying the cell types that take up these drugs is therefore crucial to understanding their effects on tumours. We have recently found that in addition to osteoclasts, other cells called macrophages can efficiently take up the drug. This may be relevant for explaining the anti-tumour effects of bisphosphonates because macrophages are often present in tumours (called tumour-associated macrophages, or TAMs in short). These TAMs can actively promote tumour growth and spreading via various mechanisms. It is therefore possible that bisphosphonates act on these macrophages and prevent them from stimulating tumour development. We will investigate this in animal models of osteosarcoma. In these models, treatment with the bisphosphonate zoledronic acid has previously been shown to have anti-tumour effects. We will now investigate whether we can detect uptake of bisphosphonate by TAMs (or any other cells in the tumour).

For this, we will use bisphosphonates that we have modified by adding a fluorescent tag so that we can see using microscopy which cells have taken up the drug. We will also determine whether the bisphosphonate is directly affecting the TAMs. We have previously revealed that the potent new generation bisphosphonates, including zoledronic acid, act by blocking a specific enzyme called farnesyl pyrophosphate synthase, or FPP synthase. This causes two distinct biochemical changes within the cell that we can measure. We propose to treat osteosarcoma-bearing mice and rats with zoledronic acid and then investigate whether we can detect these characteristic biochemical changes in the TAMs (or any other cells in the tumour). Finally, we aim to investigate whether zoledronic acid treatment of osteosarcoma-bearing animals results in a decrease in the number of TAMs that are present in the tumours. These studies will increase our understanding of how bisphosphonates exert their anti-tumour effects. This might enable the development of better treatment strategies to maximise the anti-tumour potential of these drugs in osteosarcoma and other bone cancers.

Dr Anke Jozefien Roelofs and Professor Michael John Rogers