Protein in Prostate Biopsy May Signal Higher Risk of Cancer

“A new study shows that men who have a specific marker present in their prostate biopsy may benefit from close follow-up and additional biopsies. When present, the marker—a protein found in the biopsied tissue—increases the chance that cancer will develop in the prostate. This could identify patients that need to be carefully monitored from those that do not, a decision that is currently difficult to make for clinicians. The study is published in the Journal of Clinical Oncology.


Evaluation of ERG Responsive Proteome in Prostate Cancer

“Background: Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression. METHODS: Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA…Conclusions: This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.”


Evaluation of Tissue PCA3 Expression in Prostate Cancer by RNA in situ Hybridization-A Correlative Study with Urine PCA3 and TMPRSS2-ERG

“PCA3 is a prostate-specific non-coding RNA, with utility as a urine-based early detection biomarker. Here, we report the evaluation of tissue PCA3 expression by RNA in situ hybridization in a cohort of 41 mapped prostatectomy specimens. We compared tissue PCA3 expression with tissue level ERG expression and matched pre-prostatectomy urine PCA3 and TMPRSS2-ERG levels. Across 136 slides containing 138 foci of prostate cancer, PCA3 was expressed in 55% of cancer foci and 71% of high-grade prostatic intraepithelial neoplasia foci. Overall, the specificity of tissue PCA3 was >90% for prostate cancer and high-grade prostatic intraepithelial neoplasia combined. Tissue PCA3 cancer expression was not significantly associated with urine PCA3 expression. PCA3 and ERG positivity in cancer foci was positively associated (P<0.01). We report the first comprehensive assessment of PCA3 expression in prostatectomy specimens, and find limited correlation between tissue PCA3 and matched urine in prostate cancer.”


TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

“BACKGROUND: Pre-clinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers (PCa), may be a surrogate for DNA repair status and therefore a biomarker for DNA damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). METHODS: Pre-treatment biopsies from two cohorts of intermediate-risk PCa patients (T1/T2, GS < 8, PSA < 20ng/mL) (> 7 years follow-up) were analyzed: (1) 126 patients with DNA samples assayed by array Comparative Genomic Hybridization for TMPRSS2-ERG fusion (CGH-cohort); and (2), 118 patients whose biopsies were scored within a tissue microarray (TMA) immunostained for ERG overexpression (surrogate for TMPRSS2-ERG fusion) (IHC-cohort). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using Cox proportional hazards models. RESULTS: TMPRSS2-ERG fusion by aCGH was identified in 27 patients (21%) in the CGH-cohort and ERG overexpression was found in 59 patients (50%) in the IHC-cohort. In both cohorts TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analyses. CONCLUSIONS: In two similarly-treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these PCa have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.”


New Gene-Targeting Drug is Being Studied in a Phase 2 Clinical Trial

A phase II clinical trial is being held to investigate the effect of an experimental drug, ABT-888, on castration-resistant prostate cancer (CRPC) in patients who have a genetic mutation known as a TMPRSS2:ERG gene fusion. In lab studies, ABT-888 used in combination with the prostate cancer drug abiraterone (Zytiga), helped shrink prostate cancer tumors and was especially effective for shrinking tumors that had the genetic mutation. The clinical trial is being led by investigators at the University of Michigan Comprehensive Cancer Center and conducted at multiple sites throughout the country. For more information about this trial, “A Randomized Gene Fusion-Stratified Phase II Trial of Abiraterone with or without ABT-888 for Patients with Metastatic Castration-Resistant Prostate Cancer,” call the U-M Cancer Answerline at 800-865-1125.


Phase II Trial Targeting Genetic Anomaly in Castration-Resistant Metastatic Prostate Cancer Underway

“A new clinical trial is testing whether targeting treatments to a genetic anomaly can lead to better treatments for castration-resistant metastatic prostate cancer. The trial, led by investigators at the University of Michigan Comprehensive Cancer Center, is being conducted at 11 sites throughout the country.”


Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study

“Active surveillance is used to manage low risk prostate cancer. Both PCA3 and TMRPSS2-ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort…”


PARP Inhibition Sensitizes to Low Dose-Rate Radiation TMPRSS2-ERG Fusion Gene-Expressing and PTEN-Deficient Prostate Cancer Cells

Exposure to genotoxic agents, such as irradiation produces DNA damage, the toxicity of which is augmented when the DNA repair is impaired. Poly (ADP-ribose) polymerase (PARP) inhibitors were found to be “synthetic lethal” in cells deficient in BRCA1 and BRCA2 that impair homologous recombination. However, since many tumors, including prostate cancer (PCa) rarely have on such mutations, there is considerable interest in finding alternative determinants of PARP inhibitor sensitivity…”


Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

“While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells…”