Development and validation of a gene expression assay as prognostic and predictive biomarker in prostate cancer bone metastases

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Skeletal metastases from prostate cancer are a major health burden worldwide and severely affect a patient’s quality of life. They harbor molecular alterations distinctly different from the primary tumor. Moreover, systemic treatment itself can change the molecular landscape of metastatic disease. Thus, a tissue-based biomarker evaluating molecular changes in bone metastases rather than in the primary tumor to predict prognosis or response to –targeted– therapy could be of benefit for these patients. In this proposed research project, we will apply a gene expression assay to robustly detect differentially expressed candidate genes and patterns of pathway regulation in archival formalin-fixed, paraffin embedded (FFPE) bone metastases from prostate cancer patients, because FFPE material is usually the only available material. Ninety-six candidate genes have already been identified through our preliminary work. Gene expression will be studied using a highly sensitive novel array system, that uses color-coded barcodes to detect transcripts (NanoString nCounter®) and can be custom-built. Correlation of gene expression with clinical data will subsequently identify a panel of genes with prognostic and/or predictive potential. This gene panel will undergo retrospective as well as prospective validation in tumor tissue from bone metastases. In addition, RNA from circulating tumor cells will be tested to evaluate its potential as non-invasive biomarker (liquid biopsy) for patients, for whom metastatic tissue is not available. Functional validation using two prostate cancer cell lines (VCaP/PC-3), both derived from a prostate cancer bone metastasis, will be performed. For 5-7 overexpressed genes in the gene panel, we will perform transient knockdown using siRNA to evaluate the biological consequence of overexpression. Data generated in this proposed research project will enhance our knowledge of the transcriptome of prostate cancer bone metastases and its response to systemic treatment. It will provide a translational benefit for patients with advanced prostate cancer. We expect, that our gene expression assay can act as a biomarker either on its own or in conjunction with traditional clinical or tissue-based parameters. In addition, we will show, that robust gene expression analysis is feasible from FFPE tissue from bone metastases thus facilitating further research in other tumor types that are prone to bone metastases.