Abstract
Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.
Highlights
Bone is the most common site of metastasis for many solid tumours [1]
We aim to summarise in this chapter the recent developments within the field of Cancers 2020, 12, x biomarker discovery for prediction of bone metastasis risk and their potential to influence personalised medicine initiatives
The musculoaponeurotic fibrosarcoma (MAF)-transcription factor regulates the expression of proteins including PTHrP, involved in the vicious cycle of bone destruction, and MAF amplification within primary breast cancer tumours significantly correlates with bone metastasis risk (HR = 14.5, CI = 6.4 to 32.9, p < 0.001) [18,19,35]
Summary
Bone is the most common site of metastasis for many solid tumours (in particular breast and prostate cancer) [1]. There have been substantial recent advances in treatments for bone metastasis, such as the use of bisphosphonate anti-resorptive drugs and the anti-RANKL antibody therapeutic Denosumab for treatment of breast cancer bone spread, and these have improved patient survival; there is a strong need for the discovery of biomarkers predictive of bone metastasis risk within patients. This is true for the administration of bisphosphonates, which can cause side effects including osteonecrosis of the jaw (ONJ).
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