Abstract 2503: Metabolomics identifies a caveolin-1-associated plasma glycosphingolipid and sphingomyelin signature that differentiates aggressive from indolent prostate cancer in an active surveillance cohort

Abstract

Abstract Purpose: To identify a plasma signature that can distinguish aggressive from indolent prostate cancer in patients on active surveillance based on metabolomics profiling. Introduction: The slow growth rate and low likelihood of disease progression in low-risk prostate cancer patients have led to the widely implemented active surveillance (AS) strategy. Given tumor heterogeneity, a clinical challenge is how to expand the pool of patients eligible for AS safely. Consequently, additional markers able to identify patients at increased risk of disease progression are needed. We previously identified plasma caveolin-1 (CAV1) as predictive of aggressive prostate cancer in an AS cohort. Complementary in vitro and in vivo studies demonstrated that CAV1 mediates major reprogramming of lipid metabolism, collectively suggesting that dysregulated lipid biogenesis may be associated with aggressive prostate cancer. Experimental Procedures: An integrated approach was utilized which included multi-assay untargeted metabolomics to characterize alterations in the metabolome and lipidome of conditioned media from prostate cancer cell lines following overexpression of CAV1 (LNCaP) or CAV1 siRNA knockdown (PC3M). In parallel, sera from PBCre+PTENloxp/loxp;PBCav-1+ and PBCre+PTENloxp/loxp;PBCav-1- mice were collected for metabolomics analysis to further delineate signatures related to CAV1-associated aggressive prostate cancer. We further conducted untargeted metabolomic analysis on plasma samples (n=16 per group) prospectively collected from patients with early stage prostate cancer undergoing AS who exhibited early progression (defined as upgrading of Gleason score (GS) and/or increased tumor volume on surveillance biopsy within 18 months after start of AS) or indolent disease (did not progress for a minimum of 5 years after start of AS). Patients were matched with respect to age, clinical stage, prostate-specific antigen, and GS on baseline biopsy at start of AS. We evaluated plasma samples collected at baseline (start of AS) and after 12 months. Results: Analysis of conditioned media identified a metabolomics signature with major alterations in lipid composition highlighted by CAV1-mediated elevations in lipid-raft associated sphingomyelins and glycosphingolipids. This signature was observed in patients who had early progression but not in patients with indolent disease. Importantly, this signature was observed at baseline and at least 18 months prior to disease progression on surveillance biopsy. Conclusions: We have identified a plasma-derived lipid signature that differentiates aggressive versus indolent prostate cancer in an active surveillance cohort. Our findings highlight the potential utility of altered lipid profiles as additional risk markers for aggressive prostate cancer. Citation Format: Johannes Fahrmann, Jody Vykoukal, Spyridon Basourakos, Jianxiang Wang, Jennifer Dennison, Eunice Murage, Jeri Kim, Timothy C. Thompson, Samir Hanash. Metabolomics identifies a caveolin-1-associated plasma glycosphingolipid and sphingomyelin signature that differentiates aggressive from indolent prostate cancer in an active surveillance cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2503. doi:10.1158/1538-7445.AM2017-2503