TMPRSS2-ERG status and biochemical recurrence following radiotherapy for intermediate-risk prostate cancer.

11 Background: Approximately 50% of prostate cancers (PC) contain TMPRSS2-ERG gene fusions leading to ERG overexpression. Pre-clinical data suggest that these fusions are due to altered DNA double-strand break repair status which could have therapeutic ramification for the use of radiotherapy (RT) and PARP inhibitors. The aim of this study was to correlate TMPRSS2-ERG status to biochemical failure following clinical induction of DNA breaks in the form of image-guided radiotherapy (IGRT) in intermediate-risk PC. Methods: Pre-treatment biopsies from two separate cohorts of intermediate-risk PC patients (T1/T2, GS < 8, PSA < 20ng/ml) were analyzed: 1) 126 patients assessed by array Comparative Genomic Hybridization (aCGH) for TMPRSS2:ERG fusion; and 2) 121 patients assessed by tissue microarray (TMA) for ERG expression by immunohistochemistry (IHC). All patients received IGRT with a median dose of 79.8 Gy (60-79.8 Gy). TMPRSS2:ERG status was correlated to Gleason score, T stage, initial PSA and biochemical-free relapse rate (bFRR; Phoenix definition: nadir + 2ng/ml). Results: At a median follow-up time of 6.36 years, the biochemical relapse event rate was 37% and 18% in the aCGH and IHC cohorts, respectively. ERG expression by IHC was found in 49.6% of the 121 PC. TMPRSS2-ERG status was not correlated to increased Gleason score, pre-treatment PSA or T stage. On multivariate analyses in models containing clinical factors, TMPRSS2:ERG status (either using aCGH or IHC) was not prognostic for biochemical outcome (ERG expression: HR=0.78, 95% CI: 0.33-1.85; p= 0.568; TMPRSS2-ERG fusion: HR=0.71, 95% CI: 0.35-1.41; p=0.326). Conclusions: In two separate cohorts, TMPRSS2-ERG status was not prognostic for bRFR after IGRT. Although a trend was observed, these clinical data do not support the hypothesis that these cancers have DNA repair defects that render them significantly more radiosensitive when compared to other PC. Further clinical trials are required to understand the utility of TMPRSS2:ERG status and response to DNA damaging agents, including that of PARP inhibitors. The trans-Canadian PROFIT trial is completing accrual of close to 1200 patients allowing for TMPRSS2:ERG studies in a larger RT cohort

Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma.

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP

Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP