Biomarker Of Aggressive Prostate Cancer Research Articles

The Current Landscape of Prostate-Specific Membrane Antigen (PSMA) Imaging Biomarkers for Aggressive Prostate Cancer.

The review examines the vital role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the diagnosis, staging, and treatment of prostate cancer (PCa). It focuses on the superior diagnostic abilities of PSMA PET/CT for identifying both nodal and distant PCa, and its potential as a prognostic indicator for biochemical recurrence and overall survival. Additionally, we focused on the variability of PSMA's expression and its impact on personalised treatment, particularly the use of [177Lu] Lu-PSMA-617 radioligand therapy. This review emphasises the essential role of PSMA PET/CT in enhancing treatment approaches, improving patient outcomes, and reducing unnecessary interventions, positioning it as a key element in personalised PCa management.

Anti-Müllerian hormone: a novel biomarker for aggressive prostate cancer? Emerging evidence from a prospective study of radical prostatectomies.

Prostate cancer patients are a heterogeneous group as regards the aggressiveness of the disease. The relationship of steroid hormones with the aggressiveness of prostate cancer is unclear. It is known that the anti-Müllerian hormone (AMH) inhibits prostate cancer cell lines in vitro. The aim of this study is to investigate the relationship of AMH and steroid hormones with the aggressiveness of prostate cancer. This was a prospective study of consecutive radical prostatectomy patients. We measured the following hormones: total testosterone, sex hormone-binding globulin, albumin, luteinizing hormone, follicle-stimulating hormone, estradiol, dehydroepiandrosterone sulfate, androstenedione, and AMH. The minimum follow-up after radical prostatectomy was 5years. For the aggressiveness of prostate cancer, we considered the following three variables: post-operative Gleason score (GS) ≥ 8, TNM pΤ3 disease, and prostate-specific antigen (PSA) biochemical recurrence (BCR). In total, 91 patients were enrolled. The mean age and PSA were 64.8years and 9.3ng/dl, respectively. The median post-operative GS was 7. Low AMH blood levels were correlated with higher post-operative GS (p = 0.001), as well as with PSA BCR (p = 0.043). With pT3 disease, only albumin was (negatively) correlated (p = 0.008). ROC analysis showed that AMH is a good predictor of BCR (AUC 0.646, 95% CI 0.510-0.782, p = 0.043); a cutoff value of 3.06ng/dl had a positive prognostic value of 71.4% and a negative prognostic value of 63.3% for BCR. Cox regression analysis showed that AMH is a statistically significant and independent prognostic marker for BCR (p = 0.013). More precisely, for every 1ng/ml of AMH rise, the probability for PSA BCR decreases by 20.8% (HR = 0.792). Moreover, in Kaplan-Meier analysis, disease-free survival is more probable in patients with AMΗ ≥ 3.06ng/ml (p = 0.004). Low AMH blood levels were correlated with aggressive prostate cancer in this radical prostatectomy cohort of patients. Therefore, AMH could be a prognostic biomarker for the aggressiveness of the disease.

Male-Pattern Vertex Baldness Trajectories, Chest Hair Patterns, and Odds of Overall and Aggressive Prostate Cancer.

The link between hormones and hair growth is well established. Inconsistent associations have been found between hair patterns and cancer of the prostate, a hormone-dependent organ. We assessed vertex baldness trajectories, chest hair amount, and their relationships with the odds of developing prostate cancer in a large case-control study in Montreal, Canada. In-person interviews were conducted with 1,931 incident prostate cancer cases and 1,994 population-based age-matched (±5 years) controls. Participants reported their hair patterns using the validated Hamilton-Norwood scale of baldness for 10-year increments starting at age 30, and their current amount of chest hair. Group-based trajectories were used to identify men sharing similar patterns of vertex baldness severity over adulthood. Multivariable logistic regression assessed associations between indicators of baldness (frontal, vertex, age at onset, severity, and trajectories), chest hair, and odds of prostate cancer. Vertex balding onset at age 30 was associated with increased odds of overall prostate cancer [Odds ratio (OR), 1.30; 95% confidence interval (CI), 1.03-1.64]. Men in the trajectory characterized by early moderate vertex baldness and developing severe baldness had increased odds of overall (OR, 1.42; 95% CI, 1.03-1.96) and especially aggressive prostate cancer (OR, 1.98; 95% CI, 1.21-3.22) compared with men without baldness. Men with little chest hair had higher odds of aggressive tumors than those with a moderate amount/a lot of chest hair. Early-onset moderate vertex baldness that progresses and having little chest hair may be useful biomarkers of aggressive prostate cancer. Integration of early-onset vertex balding patterns into risk prediction models of aggressive prostate cancer should be envisaged.

Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer.

The hormonal transcription factor androgen receptor (AR) is a master regulator of prostate cancer (PCa). Protein palmitoylation, which attaches a palmitate fatty acid to a substrate protein, is mediated by a class of 23 ZDHHC (Zinc-Finger DHHC motif)-family palmitoyltransferases. Although palmitoylation has been shown to modify many proteins and regulate diverse cellular processes, little is known about ZDHHC genes in cancer. Here we examined ZDHHC family gene expression in human tissue panels and identified ZDHHC7 as a PCa-relevant member. RNA-seq analyses of PCa cells with ZDHHC7 de-regulation revealed global alterations in androgen response and cell cycle pathways. Mechanistically, ZDHHC7 inhibits AR gene transcription and therefore reduces AR protein levels and abolishes AR signaling in PCa cells. Accordingly, ZDHHC7 depletion increased the oncogenic properties of PCa cells, whereas restoring ZDHHC7 is sufficient to suppress PCa cell proliferation and invasion in vitro and mitigate xenograft tumor growth in vivo. Lastly, we demonstrated that ZDHHC7 is downregulated in human PCa compared to benign-adjacent tissues, and its loss is associated with worse clinical outcomes. In summary, our study reveals a global role of ZDHHC7 in inhibiting androgen response and suppressing PCa progression and identifies ZDHHC7 loss as a biomarker for aggressive PCa and a target for therapeutic intervention.

Zinc finger protein‑like 1 is a novel neuroendocrine biomarker for prostate cancer.

Prostate‑derived calcitonin (CT) and its receptor induce tumorigenicity and increase metastatic potential of prostate cancer (PC). CT‑inducible genes in human prostate were identified by subtraction hybridization. Among these genes, zinc finger protein like 1 (ZFPL1) protein was interesting since it was abundantly expressed in malignant prostates but was almost absent in benign prostates. ZFPL1 expression was upregulated by CT and androgens, and ZFPL1 protein was secreted by prostate tumor cells through exosomal secretion. Serum levels of ZFPL1 in cancer patients were at least 4‑fold higher than those in the sera of cancer‑free individuals. Cell biology of ZFPL1 suggests its localization in Golgi bodies and exosomes, and its colocalization with chromogranin A and CD44. These results suggested that ZFPL1 is secreted by tumor cells of neuroendocrine (NE)/stem cell phenotype. The knockdown of endogenous ZFPL1 in (PC) cells led to a remarkable decrease in cell proliferation, and invasion while increasing their apoptosis. As expected, the overexpression of ZFPL1 in prostate cells had an opposite effect on these functions. The knockdown of ZFPL1 in PC cells also decreased Akt phosphorylation, suggesting the actions of ZFPL1 may be mediated through the PI3K‑Akt pathway. Moreover, the present results revealed that ZFPL1 is released by tumors cells of NE or androgen‑independent phenotype and its serum levels are significantly higher in cancer patients, suggesting that it may serve as a blood‑based non‑invasive biomarker of aggressive PC.

Biomarkers of Aggressive Prostate Cancer at Diagnosis.

In the United States, prostate cancer (CaP) remains the second leading cause of cancer deaths in men. CaP is predominantly indolent at diagnosis, with a small fraction (25-30%) representing an aggressive subtype (Gleason score 7-10) that is prone to metastatic progression. This fact, coupled with the criticism surrounding the role of prostate specific antigen in prostate cancer screening, demonstrates the current need for a biomarker(s) that can identify clinically significant CaP and avoid unnecessary biopsy procedures and psychological implications of being diagnosed with low-risk prostate cancer. Although several diagnostic biomarkers are available to clinicians, very few comparative trials have been performed to assess the clinical effectiveness of these biomarkers. It is of note, however, that a majority of these clinical trials have been over-represented by men of Caucasian origin, despite the fact that African American men have a 1.7 times higher incidence and 2.1 times higher rate of mortality from prostate cancer. Biomarkers for CaP diagnosis based on the tissue of origin include urine-based gene expression assays (PCA3, Select MDx, ExoDx Prostate IntelliScore, Mi-Prostate Score, PCA3-PCGEM1 gene panel), blood-based protein biomarkers (4K, PHI), and tissue-based DNA biomarker (Confirm MDx). Another potential direction that has emerged to aid in the CaP diagnosis include multi-parametric magnetic resonance imaging (mpMRI) and bi-parametric magnetic resonance imaging (bpMRI), which in conjunction with clinically validated biomarkers may provide a better approach to predict clinically significant CaP at diagnosis. In this review, we discuss some of the adjunctive biomarker tests along with newer imaging modalities that are currently available to help clinicians decide which patients are at risk of having high-grade CaP on prostate biopsy with the emphasis on clinical utility of the tests across African American (AA) and Caucasian (CA) men.

Unveiling genetic variant-level biomarkers for aggressive prostate cancer

Prostate cancer (PCa) represents the second most frequently diagnosed malignancy among males in the United States and ranks fourth in terms of general cancer prevalence on a global scale. A critical assessment of existing literature indicates a notable deficiency in the identification of biomarkers that are uniquely associated with aggressive forms of PCa. The principal objective of this paper is to discover biomarkers at the genetic variant level by deploying statistical methodologies to determine associations between such variants and the aggressive and lethal form of the disease. Employing the multiple comparisons technique, we identified four variants that were statistically significant at the 5 % significance level. Furthermore, we utilized Over-representation analysis (ORA) to identify the biological pathways linked with these genetic variants. To validate our findings, we employed a decision tree algorithm on an independent dataset comparing the proposed biomarkers with random subsets of variants. Results have shown that the predictive accuracy of aggressive samples was 97 % for the proposed biomarkers, while this figure dropped to 67 % when randomly selected variants were considered.

Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer.

Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.

Race Differences in Telomere Length in Benign Prostate Biopsies and Subsequent Risk of Prostate Cancer.

Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin. A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk. Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 ± 0.38 vs. 1.45 ± 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 ± 0.38 vs. 1.63 ± 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile [OR = 1.90; 95% confidence interval (CI) = 1.08-3.36]. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25-6.19). White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease. Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer.

Abstract 2702: Prostate stromal transcriptome as biomarker of aggressive prostate cancer

Abstract Background: Prostate cancer has a heterogeneous prognosis. Discovery of molecular biomarkers that improve identification of potentially lethal prostate cancer could enhance the ability to determine which patients would benefit most from immediate treatment. Most prognostic biomarkers have focused on those in prostate tumors. However, it is increasingly recognized that the tumor microenvironment contributes to cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with clinically significant, high-grade prostate cancer. Methods: We performed RNA-sequencing (Illumina TruSeq RNA Exome library preparation) of macrodissected stromal samples (adjacent to and distant from tumor) from 363 radical prostatectomy specimens from Health Professionals Follow-up Study and Physicians' Health Study participants. We performed a differential expression analysis comparing the gene expression and pathways of stroma adjacent to and distant from tumor. We also performed a cluster analysis and computed a single sample gene set enrichment analysis (ssGSEA) score to assess the association of our previously reported 25 stromal signature genes (Tyekucheva et al. 2017) to determine the association with Gleason score. Results: Eighty-eight genes as well as eight Gene Ontology pathways and fourteen Canonical pathways were differentially expressed (FDR&amp;lt;0.05) between tumor adjacent to and distant from tumor. Pathways included cell-substrate adhesion, muscle development, and cardiomyopathy. 30% of men had high-grade (Gleason score 8-10) tumors. We observed higher expression of the individual signature genes in the cluster enriched for high Gleason score tumors, and a higher stromal signature ssGSEA score was associated with high Gleason score (p=0.04). Conclusions: Pathways differentially expressed between stroma adjacent to and distant from tumor suggest known differences in cell types by location or a potential field effect. We observed that the direction of the association of the stromal signature with Gleason score agreed with our previous report. We are currently analyzing the full expression dataset to identify additional stromal genes associated with Gleason score and lethal prostate cancer, and performing multi-plex immunohistochemistry to assess stromal cell-type heterogeneity in regions of tumor and normal prostate across tissue microarrays. Citation Format: Yinglu Zhou, Chaoran Ma, Giuseppe Nicoló Fanelli, Lavinia Stefanizzi, Elizaveta Gazeeva, Lorelei A. Mucci, Massimo Loda, Svitlana Tyekucheva, Kathryn L. Penney. Prostate stromal transcriptome as biomarker of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2702.

Tandem histone methyltransferase upregulation defines a unique aggressive prostate cancer phenotype.

Histone modifications alter transcriptional gene function and participate in cancer progression. Enhancer-of-Zeste-Homologue-2 (EZH2) and Nuclear-Receptor-Binding-SET-domain2 (NSD2) methylate H3K27 and H3K36, respectively, to regulate transcription. Given the therapeutic interest in these enzymes, we investigated expression and coregulation in hormone-sensitive (HS) and castrate-resistant (CR) prostate cancer (PC). EZH2 and NSD2 levels were quantified using VECTRA analysis in HS and CRPC tissue microarrays (n = 105 + 66). Expression data from The Cancer Genome Atlas (n = 498), Memorial Sloan Kettering Cancer Center (n = 240), and Stand Up to Cancer/Prostate Cancer Foundation (n = 444) cBioportal datasets were queried, and associations between EZH2 and NSD2 and clinicopathologic variables determined. Tumour expression of NSD2, but not EZH2, increased in CRPC (p = 0.05, 0.09). Epithelial nuclei co-expressing NSD2 and EZH2 increased in CRPC compared to HSPC (69 vs 42%, p = 0.02), and in metastatic tissue relative to benign (55 vs 35%, p = 0.02). cBioportal analysis revealed collinear NSD2/EZH2 expression (Spearman = 0.57, 0.58, 0.58, all p < 0.001). NSD2/EZH2 co-expression significantly associates with clinicopathologic characteristics including grade group, stage and seminal vesicle involvement. On univariate and multivariate analysis tumours co-expressing NSD2 and EZH2 conferred increased risk of recurrence (hazard ratio: 2.6, 95% confidence inerval: 1.2-5.4, p = 0.01). Kaplan-Meier analysis revealed reduced progression-free-survival of NSD2 and EZH2 co-expression patients in datasets (p < 0.001, 0.002). Increased EZH2/NSD2 co-expression is overrepresented in CRPC, metastases and associates with shorter disease-free survival in PC patients. Coregulation of these two histone methyltransferases is a biomarker for aggressive PC and licenses them as therapeutic targets.

MAP3K7 Loss Drives Enhanced Androgen Signaling and Independently Confers Risk of Recurrence in Prostate Cancer with Joint Loss of CHD1.

Prostate cancer genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy; however, CHD1 is rarely lost without codeletion of MAP3K7. Here, we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. Although CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. Prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of prostate cancer that poses challenges to conventional therapeutic approaches. IMPLICATIONS: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor-targeted therapies.

Prognostic features of Annexin A2 expression in prostate cancer

ANXA2 (Annexin A2 or Annexin II) is a calcium dependent phospholipid binding protein with diverse cellular functions. While ANXA2 is either absent or expressed focally in the prostate epithelium of well and moderately differentiated tumours, it is highly expressed in a subset of poorly differentiated tumours. Here we examined the association between ANXA2 expression and tumour progression, with consideration of ERG expression status and patient race (Caucasian American and African American). We evaluated ANXA2 and ERG expression in index tumours by immunohistochemistry of whole mounted prostate sections and tissue microarrays derived from radical prostatectomies of 176 patients, matched for long term post-radical prostatectomy follow-up of up to 22 years (median 12.6 years), race and pathological stage. Expression of ERG and ANXA2 was analysed for correlation with grade group (GG), and pathological T (pT) stage. Kaplan-Meier estimation curves were used to examine associations between ANXA2 or ERG expression and biochemical recurrence (BCR) free survival, and distant metastasis free survival. Significant associations were found between ANXA2(+) index tumours and poorest grade groups (GG 4-5, p=0.0037), and worse pathological stage (pT 3-4, p=0.0142). Patients with ANXA2(+) prostate tumours showed trends towards earlier BCR and metastatic progression. ANXA2(+)/ERG(-) tumours were found to be associated with GG 4-5; ANXA2(-)/ERG(+) tumours, with GG 1-2 (p=0.0036). ANXA2 expression was not associated with patient race. The association between high ANXA2 expression and prostate tumours of higher grade (GG 4-5) and stage (pT 3-4) suggests a potential use for ANXA2 as a prognostic biomarker of aggressive prostate cancer.

Abstract C029: Exosomes-associated miR-5001, miR-3692 and miR-4529 are novel biomarkers for aggressive prostate cancer and associated with poor prognosis in African American patients

Abstract Background: Although microRNA (miR) profiling has been widely used to predict clinical outcomes, differential miR expressions that can segregate prostate cancer (PCa) patients based on their races and tumor aggressiveness have not been fully investigated. We aimed to determine the diagnostic and prognostic abilities of exosomal miRs to identify the aggressive phenotypes of PCa in African American (AA) men. Methods: Exosomes were isolated from blood of twenty AA and European Americans (EuA) PCa patients at low and high Gleason scores and their aged-matched healthy subjects (n=20) as well as AA and EuA normal and PCa cells. miR profiling was performed on PCa exosomes derived from blood and PCa cells. The expression level was correlated with clinical outcomes of PCa patients. The sensitivity and specificity of exosomal miRs were assessed using receiver operating characteristic (ROC) curve. Results: Results from miR profiling showed a number of exosomal miRs that were able to differentiate normal from PCa, low from high Gleason scores and AA from EuA PCa patients. These dysregulated miRs were validated in another cohort of forty PCa patients in addition to a large panel of PCa cell lines. In the validation cohort, miR-5001, miR-3692 and miR-4529 were upregulated in the exosomes derived from blood of AA compared to EuA men. These miRs were correlated with age, T-stage, residual tumor, involvement of lymph nodes, Gleason score, and overall survival of AA patients. The combination of these miRs showed high discriminatory power (AUC=0.91) for segregation of PCa patients according to their clinical outcomes. Conclusion: miR profiling identified a new set of miRs that can differentiate PCa specimens based on their race and Gleason score. The differential expression of these miRs demonstrates their potential role as biomarkers in the context of racial disparity. Further studies are warranted to determine their role in PCa at advanced stages. Citation Format: Rofaida Gaballa, Mohamed Gaballah, Hamdy E.A. Ali, Andrew S. Sholl, Hamed I. Ali, Zakaria Y. Abd Elmageed. Exosomes-associated miR-5001, miR-3692 and miR-4529 are novel biomarkers for aggressive prostate cancer and associated with poor prognosis in African American patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C029.

Genome-wide analysis of HOXC4 and HOXC6 regulated genes and binding sites in prostate cancer cells

Aberrant expression of HOXC6 and HOXC4 is commonly detected in prostate cancer. The high expression of these transcription factors is associated with aggressive prostate cancer and can predict cancer recurrence after treatment. Thus, HOXC4 and HOXC6 are clinically relevant biomarkers of aggressive prostate cancer. However, the molecular mechanisms by which these HOXC genes contribute to prostate cancer is not yet understood. To begin to address the role of HOXC4 and HOXC6 in prostate cancer, we performed RNA-seq analyses before and after siRNA-mediated knockdown of HOXC4 and/or HOXC6 and also performed ChIP-seq to identify genomic binding sites for both of these transcription factors. Our studies demonstrate that HOXC4 and HOXC6 co-localize with HOXB13, FOXA1 and AR, three transcription factors previously shown to contribute to the development of prostate cancer. We suggest that the aberrantly upregulated HOXC4 and HOXC6 proteins may compete with HOXB13 for binding sites, thus altering the prostate transcriptome. This competition model may be applicable to many different human cancers that display increased expression of a HOX transcription factor.

Abstract 3165: Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data

Abstract Introduction: Although many (~40%) of the screen-detected prostate cancers are indolent (Gleason Score &amp;lt;= 6) and pose minimal risk for progression, advanced stage prostate cancer is a lethal disease with 5-year survival rates around 29%. The challenge is to identify biomarkers for early detection of aggressive disease, when the cancer is still organ confined. Such markers would be also used to better select patients with indolent and low risk cancers for active surveillance. Material and Methods: To identify a panel of protein markers that could predict prostate cancer progression, we developed ultra-sensitive, high-pressure, high-resolution separations coupled with intelligent selection and multiplexing-selected reaction monitoring (PRISM-SRM) assays for 52 protein markers. Candidate protein markers were identified and selected from existing prostate cancer genomics data sets and validated lists of known prostate cancer drivers. The PRISM-SRM assays used heavy isotope-labeled synthetic peptides as internal standards for quantitative proteomics analysis. Study comprised of a prostate cancer patient cohort with organ confined primary tumors (N=338) presenting following post-surgery features: 53 (15.7%) metastatic progression, 124 (36.7%) biochemical recurrence (BCR), and 161 (47.6%) no progression after more than ten years of follow-up after radical prostatectomy. Index tumor region for each case was scraped from representative 10-m sections of formalin-fixed paraffin embedded (FFPE)-whole-mounted prostatectomy specimens and processed for PRISM-SRM analysis. Results: Overall, PRISM-SRM analysis of the FFPE tissue samples enabled the detection of 42 (80.8%) out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 (40.4%) of these candidates at the protein level. Kruskal-Wallis testing was used for statistical evaluation of the PRISM-SRM results and comparison of relative protein levels between the “no progression”, BCR and “metastatic progression” groups. Several prostate differentiation/androgen receptor signaling related proteins (FOLH1, PSA and NCOA) and tumor progression-related proteins (TGFB1, CCND1 and SPRC) had significantly different expression levels between the three groups, and showed initial promise in predicting progression to invasive cancer, BCR and metastasis. Conclusion: Ultra-sensitive targeted proteomics can be used to select and verify performance of early prognostic markers based on the analysis of prostatectomy specimens. The top performing markers appeared able to predict progression from organ confined cancer to BCR and metastasis. Citation Format: Yuqian Gao, Yi-Ting Wang, Hui Wang, Denise Young, Jennifer Cullen, Yingjie Song, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Inger Rosner, Karin Rodland, Isabell Sesterhenn, Shiv Srivastava, Tao Liu. Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data [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 3165.

Abstract LB-267: Transcriptomic and epigenomic analysis of metastatic castration-resistant prostate cancer and a pan-cancer analysis of its genetic signatures

Abstract Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer related deaths in the United States. The 5-year survival rate for local or regional disease is high. However, many patient’s disease will progress to the aggressive metastatic castration-resistant form of prostate cancer (mCRPC) - the estimated mortality rates of mCRPC is 19.5% for 2020 (www.cancer.org). Treatment with docetaxel or cabazitaxel alone or in combination with bevacizumab, thalidomide and prednisone increases survival rate slightly, but lead to drug resistance. The use of immunotherapy has further increased overall survival by 4-5 months. Therefore, a greater understanding of the underlying molecular mechanisms responsible for disease progression is needed.To understand and identify appropriate targets for therapy, we performed mRNA and miRNA expression studies and identified potential candidate cancer pathway genes and miRNA-mRNA pairs as biomarkers for aggressive Prostate cancer (mCRPC). Gene expression signatures were identified using differential expression (DE) analysis softwares. Spearman’s rank-based correlation and TargetScan were used to assess the association between mRNA and miRNA expression. We identified disparate mRNA and miRNA expression signatures for aggressive vs non-aggressive prostate cancers. The gene signatures were validated using the human prostate cancer patient cohort from The Cancer Genome Atlas (TCGA) database. The top ten genes that were significantly (p&amp;lt;0.0001) associated with patient survival in PCa patients, stratified by Gleason scores, were PLAU, TGFB1, SERPINE1, MET, TIPM1, ITGA3, SERPINB5, PLAUR, CDKN1A and IGF1. Ingenuity Pathway Analysis (IPA) identified the activation of angiogenesis pathway as key factor for cancer aggressiveness. Epigenetic analysis showed distinct alterations in aggressive vs non-aggressive PCa. We also identified miRNA-mRNA pairs (including PLAU- mir181) which may influence differential gene expression in advanced-stage cancers. Furthermore, we performed a pan-cancer analysis of these top PCa survival-associated genes in other solid tumor types using patient expression profiles from the TCGA database. Our results identified significant (p&amp;lt;0.05) associations of the expression of the following genes with cancer survival: PLAU (testicular, skin, lung, pancreatic and brain); TGBF1 (bladder, cervical and testicular); SERPINE1 (bladder and cervical); TIPM1 (bladder); ITGA3 (endometrial and cervical); SERPINB5 (endometrial); PLAUR (cervical); CDKN1A (bladder); and IGF1 (ovarian). In conclusion, we used genomic, transcriptomic and epigenomic approaches to identify and validate genetic signatures that may be used to further understand the molecular basis of aggressive cancers (specifically mCRPC) and develop personalized treatments with the goal of improving overall survival. Citation Format: Taraswi Mitra Ghosh, Amit Kumar Mitra, Joshua Davis, Brian Cummings, Clayton Yates, Robert Arnold. Transcriptomic and epigenomic analysis of metastatic castration-resistant prostate cancer and a pan-cancer analysis of its genetic signatures [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 LB-267.

Gadoxetate Sodium Enhanced MRI as a Biomarker for Aggressive Prostate Cancer

Gadoxetate Sodium Enhanced MRI as a Biomarker for Aggressive Prostate Cancer

ErbB-2 signaling in advanced prostate cancer progression and potential therapy

Currently, prostate cancer (PCa) remains the most commonly diagnosed solid tumor and the second leading cause of cancer-related deaths in US men. Most of these deaths are attributed to the development of castration-resistant (CR) PCa. ErbB-2 and ErbB family members have been demonstrated to contribute to the progression of this lethal disease. In this review, we focus on updating the role of ErbB-2 in advanced PCa progression and its regulation, including its regulation via ligand activation, miRNAs and protein phosphorylation. We also discuss its downstream signaling pathways, including AKT, ERK1/2 and STATs, involved in advanced PCa progression. Additionally, we evaluate the potential of ErbB-2, focusing on its protein hyper-phosphorylation status, as a biomarker for aggressive PCa as well as the effectiveness of ErbB-2 as a target for the treatment of CR PCa via a multitude of approaches, including orally available inhibitors, intratumoral expression of cPAcP, vaccination and immunotherapy.

Abstract 2573: Selection of candidate biomarkers for aggressive prostate cancer based on targeted proteomics

Abstract Mass spectrometry based targeted proteomics such as selected reaction monitoring (SRM) provides an effective, antibody-independent strategy for sensitive, specific and multiplexed verification of genomics biomarker candidates at the protein level. In order to identify a panel of proteins with the potential to predict prostate cancer progression, we have selected 52 protein candidates from existing prostate cancer genomics data sets and validated cancer drivers, and performed quantitative proteomics analysis in tissue samples using the highly sensitive PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing)-SRM approach. PRISM-SRM assays have been developed for the 52 prostate cancer biomarker candidates including: prostate cancer relevant genes and common cancer drivers. One set of 105 formalin-fixed paraffin-embedded (FFPE) whole mount prostate tissue specimens were analyzed using PRISM-SRM with heavy isotope-labeled synthetic peptides as internal standards: 20 primary tumors from patients showing metastatic progression, 37 primary tumors from patients who showed biochemical recurrence (BCR), and 48 primary tumors from patients with no BCR or metastatic progression after more than ten years of follow-up after radical prostatectomy. Overall, PRISM-SRM analyses of the FFPE tissue samples enabled the detection of 42 out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 of these candidates at the protein level. Kruskal-Wallis test of the PRISM-SRM results provided a statistical evaluation of comparison of relative protein levels among the “no progression”, BCR and “metastatic progression” groups. Prostate differentiation/AR signaling related proteins (FOLH1, PSA and NCOA) or tumor progression (TGFB1, CCND1 and SPRC) were significantly different between the three groups. These promising biomarker candidates for early detection of aggressive prostate cancer are being further evaluated, individually and in panels, in an independent cohort of 234 samples for their potential prognostic applications. In summary, PRISM-SRM provides a highly sensitive method for quantification and rapid screening of promising cancer biomarker candidates defined by multiomics platforms. Citation Format: Yuqian Gao, Hui Wang, Jennifer Cullen, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Karin Rodland, Shiv Srivastava, Tao Liu. Selection of candidate biomarkers for aggressive prostate cancer based on targeted proteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2573.