New Target for Prostate Cancer Resistant to Anti-Hormone Therapies

“Prostate cancer becomes deadly when anti-hormone treatments stop working. Now a new study suggests a way to block the hormones at their entrance.

“Researchers from the University of Michigan Comprehensive Cancer Center have found that a protein called BET bromodomain protein 4 binds to the hormone androgen receptor downstream of where current therapies work – targeting androgen receptor signaling.

“This could mean that when prostate cancer becomes resistant to current treatments, it might remain sensitive to a drug that targets BET bromodomain proteins. Results appear inNature.”

Editor’s note: The drug described in this story, JQ1, will likely soon be offered to prostate cancer patients through clinical trials.

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.”

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.”

Lineage Relationship of Gleason Patterns in Gleason Score 7 Prostate Cancer

“Gleason score 7 (GS7) prostate cancer [tumors with both Gleason patterns 3 (GP3) and 4 (GP4)] portends a significantly more aggressive tumor than Gleason score 6 (GS6). It is, therefore, critical to understand the molecular relationship of adjacent GP3 and GP4 tumor cell populations and relate molecular abnormalities to disease progression. To decipher molecular relatedness, we used laser capture microdissection (LCM) and whole-genome amplification (WGA) to separately collect and amplify DNA from adjacent GP3 and GP4 cell populations from 14 cases of GS7 prostate cancer.”