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Introduction: Loss of the tumor suppressor PTEN is associated with relapse following radiotherapy (RT) in men with prostate cancer (PCa). We have previously shown that PTEN-deficient tumors display increased monocyte and macrophage infiltration. Co-culture models have confirmed that monocyte-derived paracrine signaling factors can significantly alter the radiation response of PCa cells. The aim of this study is to identify monocyte-derived cytokines that can be therapeutically targeted in combination with RT to reduce the occurrence of relapse in men with PTEN-deficient PCa. Methods: Techniques employed included: cytokine arrays to detect radiation-induced proteins secreted from monocytes; IF and IHC on FFPE tumor sections; in vitro biological assays extending to RT-PCR, ELISA, immunoblotting and transwell migration assays; and analysis of relevant genes in the FASTMAN radiotherapy patient cohort. Results: Cytokine array analysis of monocytes with and without prior ionizing radiation exposure identified several upregulated secreted proteins - the most abundant of which was YKL40 (CHI3L1). This was further potentiated in co-culture with PCa cell lines. Secretion of YKL40 was confirmed as being monocyte-derived by ELISA and this was further supported by IF co-staining of YKL40 with a monocyte marker (F4/80) in PTEN-deficient tumour sections. Exposure of PCa cell lines to conditioned media (CM) from irradiated monocytes increased cell migration - an effect that was also observed by direct addition of rhYKL40. Previous studies have reported the role of syndecan-integrin complexes in mediating YKL40 signal transduction. Immunoblotting confirmed expression of these receptors (Sdc1 and αvβ3) on PCa cell lines. Using siRNA to knockdown Sdc1 expression inhibited YKL40-induced activation of the FAK pathway and subsequently attenuated YKL40-induced cell migration. In addition, YKL40 was shown to increase expression of genes involved in both actin cytoskeleton rearrangement and epithelial-mesenchymal transition. Use of a FAK inhibitor (PF-573228) successfully prevented the induction of these genes and attenuated the capacity of YKL40 to drive cell migration. The clinical relevance of our observations is supported by high expression of YKL40-receptor and signaling mediators in prostate cancer biopsy tissue and its correlation to increased biochemical recurrence following RT treatment. Conclusion: Use of a YKL40-pathway-targeted agent alongside radiotherapy may reduce disease recurrence in men with high-risk clinically-localized PTEN-deficient PCa by preventing radiation-induced cell migration and metastatic escape. Current and future experiments will aim to confirm this via a series of relevant in vivo studies. Citation Format: Chris W. Armstrong, Melissa LaBonte Wilson, Kelly M. Redmond, Suneil Jain, David J. Waugh. Targeting the YKL40 pathway inhibits monocyte-mediated cell migration of prostate cancer cells following radiotherapy treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3737.

299 Background: The need for validated circulating biomarkers is well recognised in advanced prostate cancer (PCa). Circulating biomarkers evaluating plasma cell-free nucleic acids and circulating tumour cells are being investigated for their clinical utility. There has been a lack of consensus with regards to analyses, reporting and clinical effectiveness of these biomarkers. A consensus meeting was held to address these issues. Methods: A multi-disciplinary panel comprising 18 international prostate cancer experts (including surgeons, medical and radiation oncologists) were consulted prior to the consensus meeting. Four key areas relating to the field of circulating biomarkers were deemed important for discussion: 1) The current utility of circulating biomarkers in 2017; 2) The clinical needs for circulating biomarkers in PCa; 3) The most pressing blood-based molecular assays required; and 4) The steps necessary for developing circulating biomarkers. Using a modified Delphi process, 50 consensus questions were pre-defined for the panel to answer by voting anonymously but publicly at the consensus meeting. Results: A consensus was declared (i.e. ≥ 75% of panellists who did not vote ‘unqualified’ or ‘abstain’ chose the same opinion) in 12/50 (24%) questions. A further 8/50 (16%) of replies were close to reaching consensus (≥ 60% of panellists choosing the same answer). The panel agreed that there is a very high and urgent unmet need for predictive biomarkers, with consensus that DNA repair biomarkers in particular are needed urgently. Metastatic PCa was identified as having the highest clinical need for development of biomarkers to measure response and as surrogate endpoints. Panellists unanimously voted that reproducibility validation studies are of paramount importance. The consensus panel also predicted that cfDNA will impact practice by 2020. Conclusions: This expert consensus identified the need for clinical trials of validated circulating biomarkers to develop predictive, response and surrogacy assays. These could have major clinical and healthcare economic implications, minimizing over-treatment and allowing the delivery of more precise patient care.