bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B19: Induction of apoptosis and antitumor activity of the AKT inhibitor AZD5363 is enhanced by combination with hormonal therapies in preclinical models of prostate cancer
Authors: Crafter Claire , Davies Barry R. , Thomas Christian , Lamoureux Francois , Greenwood Hannah , Garcia-Martinez Juan M. , Mooney Lorraine , Cosulich Sabina , Gleave Martin , Zoubeidi Amina 
Published: May 2013

Abstract
Activation of AKT by mechanisms including loss of the tumor suppressors PTEN and INPP4B is very common in prostate cancer, and has been correlated with poor prognosis and progression to androgen independent disease. Recently, a reciprocal feedback mechanism has been shown to occur between the androgen and AKT signalling axes in prostate cancer models. AZD5363 monotherapy induced apoptosis and inhibited growth of PTEN null, AR+ prostate cancer cell lines including LNCaP, C4-2 and a flutamide resistant variant of PC346C (GI50 10 – 100 nM), and showed moderate anti-proliferative activity in AR amplified, PTEN wild type VCaP cells (GI50 ∼ 1 μM). The PTEN wild type, AR negative DU-145, BPH1 and RWPE1 cell lines were relatively resistant. Monotherapy AZD5363 also caused dosedependent growth inhibition of the PTEN null, AR+ HID28 prostate cancer explant model in vivo. Treatment with AZD5363 increased expression of a panel of androgen regulated genes in LNCaP cells, whereas the same panel of genes was down-regulated when AZD5363 was combined with the novel anti-androgen MDV-3100. Combination of AZD5363 with MDV-3100 resulted in greater inhibition of growth and induction of apoptosis in vitro than monotherapy treatment with these agents, indicating a synergistic interaction. Moreover, combination of AZD5363 and bicalutamide resulted in greater efficacy than AZD5363 monotherapy in LNCaP xenografts in vivo. The data show that whilst AZD5363 has considerable monotherapy activity in AR+/PTEN null prostate cancer models, the combination with anti-androgens merits further evaluation as a possible means to achieve greater anti-tumor activity. AZD5363 is currently in Phase 1 clinical trials.
Citation Format: Claire Crafter, Barry R. Davies, Christian Thomas, Francois Lamoureux, Hannah Greenwood, Juan M. Garcia-Martinez, Lorraine Mooney, Sabina Cosulich, Martin Gleave, Amina Zoubeidi. Induction of apoptosis and antitumor activity of the AKT inhibitor AZD5363 is enhanced by combination with hormonal therapies in preclinical models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B19.
Abstract B2: Delineating the metabolic pathway to DHT in castration-resistant prostate cancer
Authors: Chang Kai-Hsiung , Li Amy , Sharifi Nima 
Published: May 2013

Abstract
After an initial response to androgen deprivation therapy (ADT) by depletion of gonadal testosterone, re-fueling androgen receptor in metastatic tumors is a critical mechanism required to drive castration resistant prostate cancer (CRPC) progression. Testosterone (T) is generally regarded as an obligate precursor for dihydrotestosterone (DHT) synthesis from adrenal precursors in CRPC and the up-regulation of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2 in CRPC is thought to convert T to DHT. Our recent findings demonstrated that an alternative pathway, namely androstenedione (AD) → 5α-androstanedione (5α-dione) → DHT, is dominant in CRPC. In this alternative pathway, AD prevails over T as a preferred substrate for 5α-reduction in CPRC. In particular, SRD5A1-mediated conversion of AD to 5α-dione is a prerequisite for converting adrenal steroids to DHT and for CRPC growth in mouse xenograft models. How 5α-dione is processed in CRPC is unknown. There are two possible routes from 5α-dione to DHT in the alternative pathway. The first route is direct 17-ketoreduction of 5α-dione by 17β-hydroxysteroid dehydrogenase-3 (17βHSD3) or 17βHSD5 (also known as aldo-keto reductase family 1, member C3, AKR1C3), both of which are up-regulated in CRPC progression. The second route is through a circuitous pathway, which requires 3-keto-reduction to 3α-hydroxyl, prior to 17-keto-reduction, namely 5α-dione → androsterone (AST) → 5α-androstane- 3α,17β-diol (Adiol) → DHT. Here, we show that ectopic expression of HSD17B5 in 293T cells efficiently converts 5α-dione to DHT, whereas AKR1C2 robustly catalyzes 5α-dione to AST and ultimately to DHT. This suggests that metabolism of 5α-dione may be determined by the relative expression and enzymatic activities of AKR1C3 and AKR1C2. These findings offer insights into the synthesis of DHT in CRPC and for the development of new therapeutic strategies.
Citation Format: Kai-Hsiung Chang, Amy Li, Nima Sharifi. Delineating the metabolic pathway to DHT in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B2.
Abstract B23: Identification of TMPRSS2:ERG-dependent regulators of AR function and differentiation status in prostate cancer
Authors: Mounir Zineb , Pagliarini Raymond , Lin Fallon , Schirle Markus , Klekota Justin , Feng Yan , Hartung Anke , Jaffe Aron , Buchwalter Gilles , Brown Myles 
Published: May 2013

Abstract
Oncogenic translocations involve the chromosomal rearrangement and fusion of two genes, which can result in either deregulated gene expression or the generation of a chimeric protein with unique oncogenic properties. Among these, fusions of the androgen-activated gene TMPRSS2 to the ETS transcription factor ERG occur in 40%–80% of prostate cancers and result in elevated expression of the ERG gene. Although a number of studies demonstrate the importance of ERG as a driver for prostate cancer development, the molecular mechanisms of ERG-mediated oncogenesis remain elusive. A deeper understanding of how ERG disrupts normal prostate biology may ultimately assist in the development of therapies that selectively target TMPRSS2:ERG -positive prostate cancer. We provide evidence that a primary role of ERG in prostate cancer is to specifically disrupt the normal regulation of androgen receptor (AR) signaling, resulting in a selective attenuation of AR's ability to promote prostate epithelial cell differentiation. We are testing the hypothesis that ERG proteins require recruitment of additional cofactors to mediate these AR regulatory functions, and that some of these protein partners may be valid therapeutic targets. Towards this end, we are working to elucidate the full network of ERG-interacting proteins, and validating which of these interactors are necessary and/or sufficient for the oncogenic and de-differentiation functions of ERG in prostate cancer.
Citation Format: Zineb Mounir, Raymond Pagliarini, Fallon Lin, Markus Schirle, Justin Klekota, Yan Feng, Anke Hartung, Aron Jaffe, Gilles Buchwalter, Myles Brown. Identification of TMPRSS2:ERG-dependent regulators of AR function and differentiation status in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B23.
Abstract B38: The histone deacetylase inhibitor LBH589 combined with radiation is an effective regimen for prostate cancer
Authors: Weiwei Xiao , Peter Graham , Carl Power , Qihan Dong , Paul Cozzi , John Kearsley , Yong Li 
Published: May 2013

Abstract
Background: Radiotherapy (RT) is one of the major curative treatment options for patients with localized prostate cancer (CaP). However radiation resistance is still the main problem for the current CaP therapy. The use of small molecular inhibitors, combined with RT provides a valuable alternative approach for cancer therapy.
Aims: The purpose of the study was to investigate the in vitro effect of LBH589 [a pan- Histone deacetylase inhibitor (HDACi)] alone and in combination with RT on the growth and survival of CaP cell lines and the possible mechanisms of radiosensitization effect.
Methods: The effect of LBH589 alone or in combination with RT on two CaP cell lines (PC-3 and LNCaP) and a normal prostatic epithelial cell line (REWP-1) was studied by MTT and clonogenic assays, cell cycle analysis, immunoblot of apoptosis-related and cell check point proteins, and DNA double strand break (DSB) repair marker. The immunofluorescence staining was used to further confirm DSB expression in treated CaP cells.
Results: LBH589 inhibited both CaP cell lines and normal prostatic epithelial cell proliferation in a time- and dose-dependent manner. Low-dose of LBH589 (IC20) combined with RT greatly improved efficiency of cell killing in CaP cells. Compared to RT alone, the combination treatment of LDH589 and RT induced more apoptosis and led to a steady increase of sub-G1 population and abolishment of RT-induced G2/M arrest. In addition, increase and persistent DSB, less activation of DNA-PKcs, Ku70, Ku80 and a panel of cell cycle related proteins were also observed in combination treatment.
Conclusions: These results suggest that LBH589 is a potential agent to increase radiosensitivity of human CaP cells. LBH589 used either alone, or in combination with RT is an attractive strategy for treating human CaP.
Grant sponsor: National Health & Medical Research Council (NH&MRC) Career Development Fellowship, St. George Hospital Cancer Research Trust Fund and China Scholarship Council (CSC).
Citation Format: Xiao Weiwei, Graham Peter, Power Carl, Dong Qihan, Cozzi Paul, Kearsley John, Li Yong. The histone deacetylase inhibitor LBH589 combined with radiation is an effective regimen for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B38.
Abstract B4: Elevated expression of c-FLIP in castrate-resistant prostate cancer antagonizes response to androgen receptor-targeted therapy
Authors: McCourt Clare , Maxwell Pamela , Mazzucchelli Roberta , Salto-Tellez Manuel , O'Sullivan Joe , Montironi Rodolfo , Scarpelli Marina , Longley Daniel , Waugh David 
Published: May 2013

Abstract
Cellular Fas-associated death domain (FADD)-like interleukin 1β-converting enzyme (FLICE) inhibitory protein (c-FLIP) is a key inhibitor of caspase 8 (FLICE)-promoted apoptosis. We have previously shown c-FLIP to be a transcriptional target of the androgen receptor (AR) and NF-κB. Accordingly, we proposed that cells with elevated expression of c-FLIP may remain viable and withstand androgen-deprivation. Expression of c-FLIP was assessed in prostatectomy tissue while in vitro experiments were performed to determine its importance in regulating response to the androgen receptor (AR)-targeted therapeutic bicalutamide. c-FLIP expression was increased in pre-malignant prostatic intra-epithelial neoplasia (PIN) (P&lt;0.001) and each of Gleason 3 and Gleason 4 prostate cancer (CaP) tissue (P&lt;0.001) relative to normal prostate epithelium. Maximal expression of c-FLIP was detected in castrate-resistant prostate cancer (CRPC) (P&lt;0.001 relative to Gleason 3/4 cancer. In vitro, siRNA-mediated silencing of c-FLIP in 22Rv1 and LNCaP cells induced spontaneous apoptosis and increased their response to bicalutamide, determined by flow cytometry, PARP cleavage and caspase activity assays. Two histone deacetylase inhibitors (HDACi), droxinostat and SAHA, were also shown to down-regulate c-FLIP expression, resulting in caspase-8 and caspase-3/7 mediated apoptosis. HDACi also potentiated the sensitivity of 22Rv1 cells to bicalutamide, while maximal apoptosis induction in LNCaP cells was not changed in the presence of bicalutamide. The combination of SAHA and bicalutamide promoted cell-specific inhibition of the AR or NF-κB signaling pathways consistent with decreased transcription of c-FLIP in these cells. Conversely, the elevated expression of c-FLIP and Bcl-2 was consistent with the insensitivity of the castrate-resistant VCaP cell line to SAHA in vitro, and the sub-optimal performance of this class of agents in castrate-resistant patients. Therefore, HDACi may prove more effective in enhancing androgen-deprivation therapy (ADT) in early-stage disease. Moreover, c-FLIP expression may serve as a predictive biomarker for androgen-deprivation strategies including bicalutamide.
Citation Format: Clare McCourt, Pamela Maxwell, Roberta Mazzucchelli, Manuel Salto-Tellez, Joe O'Sullivan, Rodolfo Montironi, Marina Scarpelli, Daniel Longley, David Waugh. Elevated expression of c-FLIP in castrate-resistant prostate cancer antagonizes response to androgen receptor-targeted therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B4.
Abstract B41: Urinary EN2 levels predict tumor volume in men undergoing radical prostatectomy for prostate cancer
Authors: Pandha Hardev , Sorensen Karina , Orntoft Torben Falck , Langley Stephen , Hoyer Soren , Borre Michael , Morgan Richard 
Published: May 2013

Abstract
Total tumor volume has been proposed as a guide to managing prostate cancer by immediate treatment versus active surveillance. We evaluated the relationship between levels of a recently described prostate cancer biomarker EN2 (Engrailed-2) in urine and cancer volume in men who had undergone radical prostatectomy for prostate cancer. Archived patient samples from the Aarhus Prostate Cancer Project, Denmark, were assessed. Pre-treatment mid stream urines, without preceding prostatic massage, were collected and stored at −80°C. Urinary EN2 levels were measured by a recently published Enzyme-linked Immunosorbent Assay (ELISA). 88 of the whole cohort of 125 men (70%) were positive for EN2 in their urine (&gt;42.5 μ/L); 38/58 (65%) of men where cancer volume data was available. No statistical relationship was found between urinary EN2 levels and serum PSA. PSA levels did not correlate with tumor stage, combined Gleason grade, total prostatic weight or cancer volume. We found a strong statistical relationship between urinary EN2 and prostate cancer volume by linear regression (p=0.0058). Furthermore, higher EN2 levels correlated with tumor stage T1 versus T2 (p=0.0272). Pre-surgical urinary EN2 levels were associated with increasing tumor stage and closely reflected the volume of cancer in prostatectomy specimens. Given the ease of collection (no prostatic massage required) and the simplicity, low cost and robustness of the assay, EN2 may become a useful biomarker in not only identifying which patients have prostate cancer but may also facilitate risk stratification by indicating the burden of tumor volume.
Citation Format: Hardev Pandha, Karina Sorensen, Torben Falck Orntoft, Stephen Langley, Soren Hoyer, Michael Borre, Richard Morgan. Urinary EN2 levels predict tumor volume in men undergoing radical prostatectomy for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B41.
Abstract B53: MiR-1 inhibits EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms
Authors: Liu Yen-Nien , Yin Juan Juan , Abou-Kheir Wassim , Hynes Paul , Casey Orla , Martin Philip , Kathleen Kelly 
Published: May 2013

Abstract
EMT is a developmental program of signaling pathways that determine commitment to epithelial and mesenchymal phenotypes. In the prostate, EMT processes have been implicated in benign prostatic hyperplasia and prostate cancer progression. In a model of Pten and TP53 null prostate adenocarcinoma that progresses via TGFβ-induced EMT, mesenchymal transformation is characterized by plasticity leading to various mesenchymal lineages and the production of bone. Here we show that SLUG is the dominant regulator of mesenchymal differentiation. As microRNAs are pleiotropic regulators of differentiation and tumorigenesis, we evaluated miR expression associated with tumorigenesis and EMT. Mir-1 and mir-200 were reduced with progression of prostate adenocarcinoma, and we identify Slug as one of the phylogenetically-conserved targets of these miRs. We demonstrate that SLUG is a direct repressor of miR-1 and miR-200 transcription. Thus, SLUG and miR-1/miR-200 act in a self-reinforcing regulatory loop leading to amplification of EMT. Depletion of Slug inhibited EMT during tumorigenesis, while forced expression of miR-1 or miR-200 inhibited both EMT and tumorigenesis in human and mouse model systems. Various miR targets were analyzed, and our findings suggest that miR-1 has roles in regulating EMT and mesenchymal differentiation through Slug and functions in tumor-suppressive programs by regulating additional targets.
Citation Format: Yen-Nien Liu, Juan Juan Yin, Wassim Abou-Kheir, Paul Hynes, Orla Casey, Philip Martin, Kelly Kathleen. MiR-1 inhibits EMT via Slugdependent and tumorigenesis via Slug-independent mechanisms [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B53.
Abstract B55: Mutation of PlexinB1 in prostate cancer
Authors: Williamson Magali , Masters John 
Published: May 2013

Abstract
Semaphorins are secreted proteins that have a role in chemotaxis and are implicated in cancer. Plexins are membrane-bound receptors for semaphorins. We have found a high frequency of mutations in the plexinB1 gene and overexpression of the protein in prostate tumours (Wong et al., 2007; PNAS 104: 19040-5) indicating a role for plexinB1 in the pathogenesis of prostate cancer. The mutations of plexinB1 found in prostate tumours are functionally significant, increasing cell motility, invasive capacity, adhesion and inhibiting cell collapse. The mutations affect signalling pathways downstream of plexinB1, inhibiting Rac, Rnd, and R-Ras binding to plexinB1 and R-RasGAP activity. The mutations have the net effect of increasing cell motility by the loss of inhibitory pathways.
We have now found that knockdown of endogenous plexinB1 in the prostate cancer cell line LNCaP inhibits anchorage-independent growth, while stimulation with semaphorin4D, the ligand for plexinB1, increases the migration and invasive capacity of LNCaP cells. These effects are reversed by expression of shRNA to plexinB1. Stimulation with semaphorin4D also results in ErbB2 and Akt activation. The opposite effects occur in the prostate cancer cell line PC3 in response to semaphorin4D. The opposite response of LNCaP and PC3 may be due to high levels of ErbB2 or c-Met expressed by the two cell lines respectively. These findings provide evidence for a subset of prostate tumours in which plexinB1 acts as a tumour-enhancing gene by activating ErbB2 and in which mutation of plexinB1 results in loss of cancer-inhibitory pathways.
Citation Format: Magali Williamson, John Masters. Mutation of PlexinB1 in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B55.
Abstract B60: Prostate-derived factor/macrophage inhibitory cytokine-1/nonsteroidal anti-inflammatory drug activated gene: A mediator of prostatic inflammation
Authors: Whitson Ramon J. , Genova Erin , Torkko Kathleen , Rosa Francisco G. La , Kelly Julie , Wilson Storey , Lambert James R. , Lucia Marshall Scott 
Published: May 2013

Abstract
Prostatic inflammation is recognized as a potential initiating and potentiating factor in the development of prostate cancer. Prostate derived factor (PDF), also known as macrophage inhibitory cytokine-1 (MIC-1) and nonsteroidal anti-inflammatory drug activated gene (NAG-1), was first cloned in a screen for genes involved in macrophage activation and as a gene induced by nonsteroidal anti-inflammatory drugs in colorectal carcinoma cells. These findings suggested that PDF may play a role in inflammatory processes. Previously, we identified an inverse relationship between PDF staining and inflammation severity using immunohistochemical (IHC) analysis in human prostatectomy samples suggesting a role for PDF in prostatic inflammation. Here, we extended these findings by examining the histologic compartment and inflammatory cell types that are potentially affected by PDF in the prostate. We found that a significant inverse relationship exists between PDF staining and CD3+ (T cells), CD4+ (T helper cells), CD8+ (cytotoxic T cells), and CD68+ (macrophages) cells in both the epithelial and periglandular compartments of the prostate. Linear correlation analysis using PDF and inflammatory cell marker staining showed moderate negative correlations with r values ranging from −0.47 to −0.52 and −0.43 to -0.46 in the epithelial and periglandular regions respectively (p &lt; 0.006). To identify a potential mechanism for the role of PDF during inflammation, we studied the effect of PDF on NF-kappaB activity in PC3 prostate cancer cells. Increased expression of PDF was accompanied by a decrease in NF-kappaB minimal promoter activation. In addition, increased PDF expression resulted in decreased activation of the NF-kappaB-regulated promoters for COX2 and IL8. These findings suggest that PDF may suppress prostatic inflammatory responses by inhibiting expression of key genes mediating inflammatory responses in human prostate.
Citation Format: Ramon J. Whitson, Erin Genova, Kathleen Torkko, Francisco G. La Rosa, Julie Kelly, Storey Wilson, James R. Lambert, Marshall Scott Lucia. Prostate-derived factor/macrophage inhibitory cytokine-1/nonsteroidal anti-inflammatory drug activated gene: A mediator of prostatic inflammation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B60.