Abstract
Abstract Introduction: There is an unmet need for liquid biopsy tests to support the management of patients with intermediate and high-risk prostate cancer (PCa). In treatment naïve patients, risk stratification by standard pathology and tissue based genomic testing can be influenced by sampling errors inherent to PCa biopsy. Exosome-based liquid biopsies are emerging as a clinically effective platform for minimally invasive and highly sensitive diagnostics for diverse types of cancer. In this project we undertake the development of a plasma exosome-based liquid biopsy to stratify patients with clinically significant PCa that may circumvent the sampling challenges associated with tissue-based genomic tests. Exosomes are small double-lipid membrane vesicles that cells actively shed into various biofluids and that provide stable packages for RNA, DNA and protein molecules. Here we take advantage of a well-developed exosomal biomarker analysis platform to profile plasma exosomal RNA markers that differentiate treatment-naïve men diagnosed with NCCN low risk vs high risk PCa as the first step in the development of a plasma exosomal liquid biopsy to support the management of patients with intermediate and high-risk disease. Methods: We compared plasma exosomal RNA profiles from 11 high-risk and 9 low-risk, treatment-naïve, biopsy-confirmed patients together with 4 healthy controls. Exosomes were isolated from 1 ml plasma samples and exosomal RNA prepared using the ExosomeDx ExoLution platform. A hybrid-capture RNA Next Generation Sequencing analysis was performed to enrich for transcripts of exons, 3’ and 5’ untranslated RNA and long non-coding RNA (lncRNA) to identify differentially expressed RNAs. Results: We detected over 10,000 protein coding genes and ~400 lncRNAs in each plasma sample using exosomal RNAseq. 273 genes were differentially expressed between high-risk vs control but not in low-risk vs control. We identified four potential plasma exosomal biomarkers of high-risk PCa. These include three protein coding mRNA transcripts that showed greater than 20-fold lower expression in plasma from high-risk in comparison to low-risk patients; TCGA data show that two of these mRNA markers are also downregulated in PCa tissue in patients with worse survival. In addition, we identified one lncRNA that showed greater than 20-fold higher expression in plasma from high-risk in comparison to low-risk patients. We also detected multiple alternate androgen receptor transcripts in plasma exosomal RNA from the high-risk patients. Together, these represent early data for potentially novel liquid biopsy RNA biomarkers for high-risk PCa. Conclusions: Here we report results of a liquid biopsy biomarker discovery study to develop an exosome-based long RNA test for to support the management of patients with intermediate and high-risk PCa. Plasma exosomal RNA provides a rich reservoir of currently untapped biomarkers for high-risk PCa. Citation Format: Sandra M. Gaston, Johan K. Skog, Benjamin Spieler, Alan Dal Pra, Radka Stoyanova, Christian Fischer, Yevgenia Khodor, Grannum Sant, Seth Yu, Vasisht Tadigotla, Sudipto K. Chakrabortty, Sanoj Punnen, Alan Pollack. Exosome-based plasma RNA biomarkers for high-risk prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3492.