Primary Bone Cancer
PROFESSOR WILLIAM FRASER
PROJECT TITLE: Single cell RNA sequencing in childhood bone cancer circulating tumour cells
PROJECT TIMESCALE: 1 June 2017 – 31 May 2020
PRINCIPLE INVESTIGATOR: Professor William Fraser
SENIOR RESEARCH ASSOCIATE: Dr Darrell Green
Bone is an endocrine organ with key biological functions. The skeleton produces hormones and cytokines, such as FGF23 and osteocalcin, which regulate an extensive list of physiological functions. Some of these functions include glucose metabolism, blood cell production and calcium/phosphate metabolism. As with other organs in the body, the cells that make up the bone can become cancerous. Primary bone cancer, or cancer which starts in the bone, is a rare tumour mostly diagnosed in children and young adults. Because of the rarity of this type of cancer research is underfunded when compared to other “adult” cancers such as breast, prostate and bowel. Treatment is limited to conventional chemotherapy and surgery which often involves limb amputation. The limited knowledge of bone cancer and the lack of treatment options is reflected in the figures in that five year survival is as low as 50% even when diagnosed early. In cases where the cancer has already spread by the time of diagnosis the five year survival rate drops to 25%.
Bone cancer can be divided into different types depending on the type of cell that has become cancerous and the specific changes within its DNA. (Fig.1 below)
Fig. 1. Bone contains a mix of different cell types – osteoblasts, osteoclasts, osteocytes and chondrocytes. Mesenchymal stem cells (in grey) are cells that reside within the bone, producing the different bone cell types as and when they are required throughout a person’s life (in white). It is thought bone cancer arises when a mesenchymal stem cell has a mutation (a change in the DNA sequence) in a particular type of gene called a ‘tumour suppressor gene’ ( in dark red). Other mutations accumulate within the cancer cells that the defective mesenchymal stem cell produces (in light red), which determines what type of bone cancer will arise if a tumour develops – osteosarcoma, Ewing sarcoma and chondrosarcoma.
Not all changes contribute to tumour progression. Some changes are meaningless by-products of the disease which can obscure scientific findings as to what exactly is causing the cancer. More specifically there is huge “background noise” hiding the critical genes and central drivers of the cancer when whole tumours are studied. Circulating tumour cells (CTCs) are cancer cells that are largely driven by “critical genes” only, having developed mechanisms to move out of a primary tumour, enter into the blood and propagate secondary tumours elsewhere in the body (Fig. 2). This process, known as metastasis, is the leading cause of cancer related death.
For every billion blood cells there is 1 CTC in a cancer patient. It has recently become possible to isolate CTCs more easily. Molecular analysis of CTCs rather than whole tumours may identify the meaningful genes and drivers contributing to the spread of secondary tumours. The genes discovered in CTCs may infer which treatment is best as particular genes are known to respond differently to different drugs. For example, cancer cells displaying different forms of the EGFR gene are known to respond well to a drug called Gefitinib. Gefitinib has been shown to keep cancer at bay and has fewer side effects when compared to conventional chemotherapy. Unfortunately cancer cells almost always develop resistance to treatment and do this by employing the use of new genes and drivers to spread. Molecular analysis of CTCs will alert the oncologist as to when the time is right to deliver the next targeted treatment. This approach may stop cancer spread, deplete tumours of their most aggressive cells and reduce the need for invasive surgery to remove the tumour.
Because osteosarcoma is rare, it is common for scientists to use animal models to perform research and test new treatments. These studies often involve implanting human bone cancer into mice and rats before subjecting these animals to research. We believe that by spending time putting together a team of experts from across the UK we can form a specialist team to work with patients and reduce the use of animals in research.
In the new study funded by The Humane Research Trust a collaboration has been developed between the Norwich Research Park which houses world leading research facilities, clinical and non-clinical expertise, including clinical trial units and state of the art genomics platforms and The Royal Orthopaedic Hospital in Birmingham, who are one of the largest specialist orthopaedic hospitals in Europe with a dedicated oncology unit. The new study will use the latest technology to identify gene expression changes in CTCs with the aim of (i) understanding the biology of osteosarcoma spread (ii) using precision medicine to “fix” the spread and stop it in its tracks. We hope this targeted strategy will improve the quality of osteosarcoma treatment by reducing and replacing the future use of conventional chemotherapy and lowering the rate of limb amputation.