Prostate cancer liquid biopsy: Plasma and urine extracellular vesicles profiles for early detection and risk stratification.
Rodney Ouellette, Atlantic Cancer Research Institute
Serum PSA levels have been utilized as a prostate cancer biomarker for over 21 years. But, PSA has intrinsic limitations. The information from PSA level study does not give enough information about the tumor so that clinicians and patients confidently choose between active surveillance strategy and biopsy. Up to 50% of men who have undergone surgical or other therapeutic interventions to treat their PCa likely had indolent, slow-growing tumors that would never have become a threat to their lifespan or health. For those patients the subsequent therapies and prostate tissue biopsies are unnecessary. Hence appropriate incorporation of biomarkers into clinical practice can reduce the unnecessary stress, depression and anxiety of patient, his relatives and caregivers. It also elevates the cost of treatment. Our preliminary data reflects that urinary EV (mRNA+ miRNA) biomarker panel can distinguish biopsy negative and biopsy positive patients with high accuracy (AUC=0.85) and 88.5% specificity. On top the information holds promise to discriminate between indolent and more aggressive, high-risk prostate tumors. The research described in this proposal will use blood sample from 12 patients (6 patient with Gleason score 6 and 6 patients with Gleason score ≥7). The different level of cancer samples will give our team the opportunity to study biomarker to distinguish between different stages of cancer. We have 6 plasma samples who does not have cancer but went through the same procedure as patients.
Prostate cancer is one of the leading causes of cancer-related death among Canadian men. The standard of care for early detection and surveillance is a blood-based PSA test, which has mixed results and has led to potential over-diagnosis and over-treatment. We have recently developed a urine-based test, when compared to a similar commercially available urine-based test, performs better and is able to predict high-grade prostate cancer [Benzina S et al. (manuscript in submission)]. Our urine-based test utilizes our patented EV capture peptide, Vn96, and the measurement of mRNA (PCA3, PSA, GOLM1, ANXA3, CD24, TMPRSS2-ERG, PSCA, SLC45A3, PSMA, TMPRSS2, ITSN1, GSTM4, CFD) and miRNA (574-3p, 375, 141, 21) from the captured RNA. The objective of our study is identification of small non coding RNAs (snc RNAs) in plasma extracellular vesicles for early detection of prostate cancer (PCa) and distinguish low risk from aggressive Prostate cancer (PCa) at the time of diagnosis. To fulfill the objectives we set two aims: Aim 1: Identification of biomarker (mRNA, miRNA, tRFs) from plasma EVs by Next Generation Sequencing (NGS) Aim 2: Validation of NGS result by qPCR. Recently very preliminary results from our lab with prostate cancer cell lines showed that ten tRNA derivatives (tRNA-Gly-CCC-5-1, tRNA-Val-CAC-3-1, tRNA-Val-AAC-2-1, tRNA-Val-CAC-7-1, tRNA-Glu-TTC-3-1, tRNA-Val-CAC-2-1, tRNA-Glu-TTC-8-1, tRNA-Glu-TTC-4-2, tRNA-Glu-TTC-4-1, tRNA-Val-AAC-5-1) up regulated in prostate cancer cell line (LNCaP) compared to control cell line (HPrEC). We propose to analyze plasma for identification of sncRNAs (specially miRNA and tRNA derivatives) in plasma extracellular vesicles for early detection of prostate cancer (PCa) and distinguish low risk from aggressive PCa at the time of diagnosis.
Impact on prostate cancer patients:
Patients with PCa restricted in prostate only normally treated with radical prostatectomy or primary radiation therapy and around 70% of those patients are cured. But, approximately 30% of patients require androgen deprivation hormone therapy when PCa relapse. This relapsed disease is called castration-resistant prostate cancer (CRPC) and one of the most difficult cancers to treat as all of the conventional antiandrogen therapies fail to work against CRPC. The enormous genetic heterogeneity of CRPC and highly variable responses to antiandrogens limit the clinical benefit of hormone therapy, highlighting the importance of developing novel biomarkers for CRPC. The development of minimally invasive biomarker tests to improve accuracy in discerning aggressive from indolent PCa and treatment response would facilitate the correct stratification of patients towards curative or surveillance arms of therapy and reduce over-treatment. Furthermore a biomarker test that improves upon detection of progressing disease could reduce the numbers of repeat biopsies required for patients within active surveillance programs.