Novel biomarkers for bone metastases – from mechanism to analytics and back

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Bone metastases due to breast cancer are frequent and largely incurable complications in up to 80% of patients at late stage and are associated with fractures, pain, poor quality of life, and poor survival. Even before diagnosis, single circulating tumor cells (CTCs) leave the primary tumor and home to bone, where they colonize the bone marrow as disseminated tumor cells (DTCs). Subsequently, these cancer cells establish osteolytic lesions in a mutual interaction with bone-resorbing osteoclasts, the vicious cycle, where bone is destroyed while tumors expand. Biomarkers reflecting bone turnover are currently used in clinical decision-making and to monitor bone-targeted therapies both in clinical trials and daily practice. However, these biomarkers are rather descriptive and do not reflect features like bone quality and strength, bone mineral density as well as the local activity of bone regulating cells under normal or disease conditions. In addition, preanalytical (circadian and dietary influence) and methodological limitations (interference) impair their use in daily practice.In recent years, a wide spectrum of biologically active proteins with specific roles in the regulation of bone metabolism has been identified. These proteins have also been linked to the pathogenesis of bone metastases secondary to breast and prostate cancer as well as myeloma bone disease. However, the prognostic value of these biomarkers in breast cancer metastases to bone has not been assessed. We have extensive expertise in the fields of osteooncology, and preclinical and molecular models of human bone disease with a track record of >10 years with biomarkers of bone metabolism. Funded by the DFG Research Unit 1586 SKELMET, we have recently identified osteoprotegerin (OPG) as a poor prognosis marker in patients with breast cancer.In this proposal, our aims are to (i) comprehensively analyze the role of OPG in breast cancer metastasis to bone using a fully established spectrum of state-of-the-art cell culture and in vivo models and to (ii) identify novel biomarkers in breast cancer and bone metastases with a focus on bone sialoprotein, periostin, and myostatin using well-characterized patient cohorts. To optimize the translational output, we will closely collaborate in this transfer project with Immundiagnostik, a leading diagnostics company in the osteooncology research field and long-term partner with a track record of joint projects and publications. This collaboration will benefit from the synergy of expertise in bone and cancer biology, biomarkers, as well as application-oriented technology. The results of the study will help to better predict the onset or stage of bone metastasis in breast cancer, allowing a more precise risk stratification, which is expected to translate into improved outcome of patients with bone metastases.