Biomarkers for Diagnosis and Prognosis of Prostate Cancer

Since its discovery, elevated prostate-specific antigen (PSA) has been the measurement to indicate possibility of prostate cancer, as well as biochemical recurrence following treatment. Although PSA has led to decrease in prostate cancer–related mortalities, PSA is a nonspecific prostate cancer biomarker reflective of other prostate-related conditions such as benign prostatic hyperplasia (BPH), resulting in a high false-positive rate. This has led to overtreatment of men with clinically insignificant disease. While most prostate cancer patients have slowly progressive disease and should be treated conservatively, roughly 10% of patients will progress to have metastatic disease, of which the majority of prostate cancer deaths can be attributed. Stratifying these patients based on prognosis so that they may benefit from aggressive treatment is critical to their survival. Biomarkers for prostate cancer diagnosis and subsequent prognostic screening have significantly advanced this field. Here, we review some of the current blood, tissue, and urine biomarker tools used to measure an array of molecules including DNA, RNA, protein, or even epigenetic modifications. Utilizing the technologies described here, as well as looking to the future, correct early identification of prostate cancer with powerful prognostic value is much closer than ever before

Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

Mediating Prostate Cancer Metastasis Through the MicroRNA Cluster MiR-23b/-27b

Deregulation of microRNAs contributes to progression and metastasis of prostate and other cancers. MiR-23b and miR-27b, encoded in the same miR cluster (miR-23b/-27b), are down-regulated in human metastatic prostate cancer compared to primary tumors and benign tissue. Expression of miR-23b/-27b decreases cell migration, invasion and results in anoikis resistance. Conversely, antagomiR-mediated miR-23b and -27b silencing produces the opposite result in a more indolent prostate cancer cell line. However, neither miR-23b/-27b expression nor inhibition impacts prostate cancer cell proliferation or viability suggesting that miR-23b/-27b selectively suppresses metastasis. To examine the effects of miR-23b/-27b on prostate cancer metastasis in vivo, orthotopic prostate xenografts were established using aggressive prostate cancer cells transduced with miR-23b/-27b or non-targeting control miRNA. While primary tumor formation was similar between miR-23b/-27b-transduced cells and controls, miR-23b/-27b expression in prostate cancer cells decreased seminal vesicle invasion and distant metastases. Gene expression profiling identified the endocytic adaptor, Huntingtin interacting protein 1 related (HIP1R) as being down-regulated by miR-23b/-27b. Ectopic HIP1R expression in prostate cancer cells inversely phenocopied the effects of miR-23b/-27b overexpression on migration, invasion, and anchorage-independent growth. HIP1R rescued miR-23b/-27b mediated repression of migration in aggressive prostate cancer cells. HIP1R mRNA levels were decreased in seminal vesicle tissue from mice bearing miR-23b/-27b-transduced prostate cancer cell xenografts compared with scrambled controls, suggesting HIP1R is a key functional target of miR-23b/-27b. In addition, depletion of HIP1R led to a more rounded, less mesenchymal-like cell morphology, consistent with decreased metastatic properties. Together, these data demonstrate that the miR-23b/-27b cluster targets hip1r and functions as a metastasis-suppressor in pre-clinical models of prostate cancer

Abstract 1467: The miR-23b/-27b cluster decreases metastasis of aggressive prostate cancer

Abstract Metastasis is responsible for the vast majority of prostate cancer deaths. As such, it is essential to understand the mechanisms driving prostate cancer to this lethal stage. Deregulation of microRNAs is increasingly implicated in the progression and metastasis of prostate and other cancers. MiR-23b and miR-27b, two members of the same miR cluster (miR-23b/-27b), are down-regulated in human metastatic, castration resistant prostate cancer (CRPC) as compared to primary tumors and benign tissue. However, the role of the miR-23b/-27b cluster is not fully understood, particularly in metastatic disease. Interpretation of existing data is complicated by the analysis of the individual effects of miR-23b and miR-27b even though these miRs are co-transcribed and coordinately expressed. The primary goal of our study is to determine the effects of miR-23b/-27b on metastatic processes in vitro and in vivo. Ectopic expression of miR-23b/-27b in two aggressive prostate cancer cell lines decreases migration, invasion and anchorage-independent growth. Conversely, inhibition of miR-23b/-27b using specific antagomirs in relatively indolent prostate cancer cells promotes increased invasion and migration. E-cadherin protein and mRNA levels were inversely related to miR-23b/-27b levels. In contrast, manipulation of miR-23b/-27b levels had no effect on prostate cancer cell proliferation in any of the tested cell lines. These findings suggest that miR-23b/-27b is specifically linked to metastasis suppression. The Rho GTPase, Rac1, is hyperactive in CRPC cell lines and patient samples. Since Rac1 promotes invasion and migration, we investigated the effects of miR-23b/-27b expression and inhibition on Rac1 activity. Ectopic expression of miR-23b/-27b in aggressive prostate cancer cell lines significantly attenuates active Rac1 while having no effect on total Rac1 levels. Conversely, inhibition of miR-23b/-27b in less aggressive prostate cancer cells increased Rac1 activity but not Rac1 levels. We further examined the effects of miR-23b/-27b on prostate cancer metastasis in vivo. Metastatic prostate cancer cells expressing luciferase and miR-23b/-27b or a scrambled control, were injected into the ventral prostates of nude mice. Orthotopic tumor formation and metastases were assessed by bioluminescence imaging. Metastatic tumor burden was greatly decreased in the tumors derived from miR-23b/-27b expressing cells. Taken together, these data demonstrate that expression of miR-23b/-27b exerts metastasis-suppressing effects in vitro and in vivo. The miR-23b/-27b cluster may be a useful biomarker of poor prognosis in addition to having therapeutic potential in advanced, metastatic prostate cancer. Citation Format: Meghan A. Rice, Reema Ishteiwy, Thirupandiyur Udayakumar, Derek Dykxhoorn, Kerry L. Burnstein. The miR-23b/-27b cluster decreases metastasis of aggressive prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1467. doi:10.1158/1538-7445.AM2014-1467</jats:p

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies.