bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4139: Diagnostic performance of the F-18 labeled bombesin analog BAY 86-4367 in patients with primary prostate cancer
Authors: Schäfer Niklaus , Valencia Ray , Borkowski Sandra , Geissler Eva , Kristiansen Glen , Rohde Beate , Bacher-Stier Claudia , Krause Bernd J. , Hany Thomas F. 
Published: August 2014

Abstract
Purpose: BAY 86-4367 is a new directly F-18 labeled, synthetic bombesin analog (3-Cyano-4-[18F]fluorobenzoyl-Ala(SO3H)-Ala(SO3H)-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) with antagonistic properties, targeting Gastrin-releasing-peptide receptors (GRPr). The aim of this proof of mechanism (PoM) study is to demonstrate the feasibility, safety, tolerability, biodistribution and diagnostic performance of the PET tracer BAY 86-4367 in patients with primary prostate cancer.
Methods: 5 patients with non-treated primary prostate cancer (PSA range 7 to 24 µg/l) were prospectively included in the study. All patients had standardized biopsy proven primary prostate cancer with Gleason scores ranging from 6 (3+3) to 9 (4+5). All patients had standardized sequential dynamic and static PET/CT using the F-18 labeled tracer BAY 86-4367 for primary staging. Safety data (vital signs, ECG, adverse effects) were assessed in all patients. Four patients had a prior PET/CT scan with F-18 choline. Patients were scheduled for prostatectomy of primary prostate cancer. Full prostate samples were histopathologically analyzed to further confirm the imaging localisation data.
Results: The tracer BAY 86-4367 was well tolerated after injection of ∼300 MBq and a peptide mass dose &lt;40 µg per patient. Safety data showed no relevant changes in the sequential blood values, electrocardiograms, urine testing or physical examination. Malignant lesions were depicted in 3/5 patients with the F-18 labeled BAY 86-4367 tracer. Biopsy verified the correct tumor localisation of these imaging findings. In two patients with histologically proven primary prostate cancer, BAY 86-4367 showed no active accumulation in the prostate. F-18 choline PET/CT was performed in 4/5 patients with positive signals in all 4 patients. Correlation with biopsy showed correct localisation of F-18 choline in tumor tissue. However, there was false positive F-18 choline accumulation in benign hyperplasia of the prostate.
Conclusion: PET imaging with the F-18 labeled bombesin analog BAY 86-4367 is safe. The tracer BAY 86-4367 correctly depicts primary prostate cancer in a subset of patients. However, diagnostic accuracy of bombesin analogs in GRPr imaging needs to be further explored.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4139. doi:10.1158/1538-7445.AM2011-4139
Abstract LB-294: GBR 500, a monoclonal VLA-2 antibody inhibits tumor and metastasis growth but not extravasation in a prostate cancer animal model
Authors: Attinger Antoine , Hou Sam , Pesenti Enrico A. , Mancini Laura , Mottl Harald 
Published: August 2014

Abstract
VLA-2 is the alpha2beta1 integrin which mediates interactions of cells with collagens, laminin and other extracellular matrix components. In tumor cells, VLA-2 plays a role in neovascularization, tumor-stroma interactions and metastasis.
The objective of this study was to understand the role of VLA-2 in extravasation and metastasis of prostate cancer cells. VLA-2 may play a role by mediating extravasation through the basement membrane or in supporting metastasis growth in the stroma through interactions with the extracellular matrix.
We assessed whether GBR 500, a monoclonal IgG4 antibody directed against the alpha2 subunit of the alpha2beta1 integrin heterodimer could prevent extravasation and metastasis formation. GBR 500 is currently undergoing clinical phase I studies. The antibody binds to human but not to mouse VLA-2.
In an orthotopic mouse Xenograft model using a DU145-luc cell line we explored the importance of VLA-2 for tumor growth by inhibition of VLA-2 with a combination of GBR 500, specific for human VLA-2 and HA1–29, specific for mouse VLA-2. Bevacizumab was used as positive control.
In vitro, GBR 500 inhibits the binding of PC3 prostate cancer cells to collagen with an EC50 of 0.035 μg/ml. To study the impact of VLA-2 on extravasation in a PC3-luc metastasis model we blocked VLA-2 with GBR 500 before injection of tumor cells and by pre-dosing mice with a 50 mg/kg dose i.v.
This group of mice was compared with two groups of mice which where treated i.p with GBR 500 twice a week at 1mg/kg and 5 mg/kg. The positive control was bevacizumab at 5mg/kg.
Results: Bi-weekly treatment with GBR 500 5 mg/kg successfully slowed tumor growth and was as effective as bevacizumab 5 mg/kg treatment. Pre-incubation and pre-dosing with VLA-2 did not affect the extravasation and metastases formation.
Conclusion: : Inhibition of tumor growth was exhibited by VLA-2 in a prostate cancer PC3-luc metastasis model. This inhibition has no apparent effect on the extravasation of PC3 cells indicating that the antibody acts in the tissue by preventing establishment of metastases. The potency of GBR 500 in this model is comparable to bevacizumab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2011-LB-294
Abstract LB-356: An siRNA screen identifies Rsk1 as a key modulator of lung cancer metastasis
Authors: Lara Romain , Mauri Francesco A. , Taylor Harriet , Derua Rita , Shia Alice , Gray Colin , Nicols Alastair , Shiner Robert J. , Schofield Edward , Bates Paul A. , Waelkens Etienne , Dallman Maggie , Lamb Jonathan , Zicha Daniel , Downward Julian , Seckl Michael J. , Pardo Olivier E. 
Published: August 2014

Abstract
Lung cancer is the commonest cancer killer worldwide. The appearance of distant metastasis is one of the main reasons for failing to cure patients with this disease. To address the underlying molecular mechanisms that regulate cancer cell motility, we performed an automated kinome-based RNA interference screen in the non-small cell lung cancer (NSCLC) cell line A549. We studied changes in cell migration patterns using timelapse microscopy and automatic tracking. Mathematical analysis of the obtained cell tracks provided information on migration speed and distance. 48 kinases were identified that were previously unknown to regulate cell motility. Among our candidates, were several members of the ribosomal S6 kinase (Rsk) family. In particular, Rsk1 silencing increased, while Rsk2 and 4 downregulation decreased, cell motility. These effects correlated with changes to the actin cytoskeleton as well as decreased E-cadherin and increased Vimentin expression levels. A secondary 3-dimensional invasion screen for our candidates confirmed that Rsk1 downregulation increased the invasiveness of A549 cells. In silico analysis and biochemical experimentation revealed that Rsk1 interacted with the actin regulators Vasp and Mena. This correlated with the ability of Rsk1 to phosphorylate Vasp on Thr-278, a site regulating Vasp-mediated actin dynamics. Moreover, Rsk1 silencing enhanced the metastatic behaviour of A549 cells in vivo using a zebrafish xenograft model. Importantly, immunohistochemical staining validated Rsk1 down regulation in metastatic lung cancer samples compared to isogenically matched primary tumours. Moreover, patients with Rsk1-negative lung primary tumours showed an increased number of metastatic lesions as well as an increase in Rsk2 and/or Rsk4 staining establishing Rsk family members as strong determinants of lung cancer cell metastasis and potential predictive markers for the progression of this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-356. doi:10.1158/1538-7445.AM2011-LB-356
Abstract 1000: ATP7A mutation reduces resistance to chemotherapy agents in vitro and in vivo.
Authors: Zhu Sha , Petris Michael J. 
Published: August 2014

Abstract
The Menkes protein (ATP7A), a copper-translocating P-type ATPase, is responsible for the loading of copper from the cytosol into secretory compartments of the cell for incorporation into newly synthesized copper-requiring enzymes. Previous studies using cultured cell lines have suggest that ATP7A is able to modulate cellular accumulation of cisplatin, a platinum-containing chemotherapy agent. In this study, we generate isogenic ATP7A-WT and ATP7A-knockout mouse embryonic fibroblast cells line pairs. We demonstrate that ATP7A deletion significantly decreases cellular resistance to cell cycle non-specific platinum agents, cisplatin & carboplatin and cell cycle specific alkaloid agent, vincristine sulfate. In addition, loss of ATP7A sensitizes xenograft tumor growth to cisplatin toxicity. These findings identify the ATP7A copper transporter as an active participant in multidrug resistance pathways in vivo, underscoring this transporter as a potential drug target to augment platinum-based chemotherapeutics.
Citation Format: Sha Zhu, Michael J. Petris. ATP7A mutation reduces resistance to chemotherapy agents in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1000. doi:10.1158/1538-7445.AM2013-1000
Abstract 1001: Elevated fibroblast growth factor-inducible 14 (Fn14): a novel therapeutic target in gastric cancer.
Authors: Kim Seon-Young , Kwon Oh-Hyung , Kim Yong Sung , Noh Seung-Moo , Song Kyung-Sang 
Published: August 2014

Abstract
Chemoresistance is one of the most serious problems in the cancer treatment. Here we show that Fn14 is a gene that promotes resistance to 5-fluorouracil (5-FU) in gastric cancer. We found that 5-FU treatment augmented Fn14 expression at both the RNA and protein level in gastric cancer cell lines, and that knock-down of Fn14 using shRNA accelerated sensitivity to 5-FU. We then investigated the underlying mechanism of Fn14-mediated chemoresistance. 5-FU treatment resulted in up-regulation of Fn14 expression as well as Bcl-xL by translocation of NF-κB to the nucleus and subsequent transcriptional activation. To examine whether NF-κB binds directly to Fn14 promoter, we performed luciferase assay. As a result, 5-FU treatment augmented Fn14 promoter activity, while increased activity of Fn14 reporter gene was reduced by NF-κB inhibitor and NF-κB knock-down by siRNA. In chromatin immunoprecipitation assay, we revealed that 5-FU treatment enhanced NF-κB binding to Fn14 promoter, indicating that NF-κB activation by 5-FU was the principal event for Fn14 up-regulation followed by resistance to 5-FU in gastric cancer. Our results suggest that Fn14 is a novel therapeutic target, and that dysfunction of Fn14 combined with 5-FU treatment is an effective therapeutic strategy to overcome resistance to 5-FU of gastric cancer patients.
Citation Format: Seon-Young Kim, Oh-Hyung Kwon, Yong Sung Kim, Seung-Moo Noh, Kyung-Sang Song. Elevated fibroblast growth factor-inducible 14 (Fn14): a novel therapeutic target in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1001. doi:10.1158/1538-7445.AM2013-1001
Abstract 1002: Deletion of GCN5 confers sensitivity to the histone deacetylase inhibitor CG-1521.
Authors: Gaupel Ann-Christin , Begley Thomas J. , Tenniswood Martin P. 
Published: August 2014

Abstract
Aberrant histone post-translational modifications including acetylation are common in human cancers and result in dysregulation of gene expression. Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) and HDAC inhibitors (HDACi) are promising anticancer therapeutics. Our laboratory has focused on studying the effects of hydroxamic acid based HDACis including TSA, SAHA and CG-1521. We have previously shown that CG-1521 induces cell cycle arrest and apoptosis in various cell lines of breast and prostate cancer.
The purpose of this study is to gain insight into the mechanism of the HDAC inhibitor CG-1521 and identify potential combinatorial drug targets. We have employed a whole genome yeast deletion library screen to determine which gene deletions confer sensitivity and resistance to CG-1521. 407 sensitive and 80 resistant strains were identified. We used gene ontology enrichment analysis to determine which pathways are modulated by CG-1521. Sensitive strains are highly enriched in processes regulating chromatin remodeling and transcription. The list of resistant strains contains many genes involved in the regulation of transcription and tRNA modification. Deletions of components of the SAGA HAT complex are highly overrepresented in the sensitive strains, including the catalytic subunit Gcn5. It appears that the SAGA complex is required to reduce the effect of CG-1521 on cell growth. Cell cycle analysis shows that CG-1521 treatment in Saccharomyces cerevisiae results in G1 arrest in both the wild type and the gcn5Δ strain. The gcn5Δ strain displays increased sensitivity to CG-1521 induced cell death compared to the wild type strain. In contrast to the highly sensitive gcn5 deletion strain, a yeast strain expressing a catalytically inactive variant of the Gcn5 protein is less sensitive to CG-1521. This indicates that functions other than the acetyltransferase activity are partially sufficient to attenuate the effects of CG-1521.
We have identified that disruption of the SAGA HAT complex can sensitize cells to CG-1521 and are validating whether loss of the human Gcn5 homologs, Gcn5 and PCAF, also confers sensitivity to CG-1521 in breast cancer cell lines. Taken together, our work suggests that the combination of selective HAT and HDAC inhibitors might be effective for the treatment of cancer.
Citation Format: Ann-Christin Gaupel, Thomas J. Begley, Martin P. Tenniswood. Deletion of GCN5 confers sensitivity to the histone deacetylase inhibitor CG-1521. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1002. doi:10.1158/1538-7445.AM2013-1002
Abstract 100A: Prognostic significance of the expression levels of target genes of retinoic acid in hepatocellular carcinoma.
Authors: Shiota Goshi , Kanki Keita 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC), a common and fatal malignancy, is increasing in incidence in developed countries. HCC generally arises in cirrhotic livers and has a poor prognosis because of the high incidence of disease recurrence after curative treatment. To improve patient prognosis, identification of new targets for early detection, chemoprevention, and treatment is urgently required.
In the pathogenesis of chronic liver disease, activation of hepatic stellate cells accompanied by decreasing vitamin A storage has been observed, leading to development of the hypothesis that the loss of retinoid content is closely associated with the progression of chronic liver diseases including HCC. In a previous study, we observed steatohepatitis and HCC development in transgenic mice that express a dominant-negative form of RAR in a liver-specific manner. These findings indicate that identifying genes regulated by retinoid signaling is important for understanding the molecular mechanisms of liver disease leading to hepatocarcinogenesis.
To identify novel retinoic acid (RA)-responsive genes facilitating the antitumor activity of RA in hepatocellular carcinoma (HCC), we performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs), chromatin immunoprecipitation analysis of the retinoic acid receptor (RAR), and gene expression analysis. We identified 201 candidate genes with promoter regions containing consensus RAREs using in silico analysis. We identified 126 candidate genes with functional RAREs which are occupied by RAR and finally selected 26 RA-responsive genes in 2 human HCC and 1 human breast cancer cell lines. Among these genes, we identified OTU domain-containing 7B (OTUD7B) and frizzled family receptor 4 (FZD4) as potential inducers of RA-mediated antitumor activity. OTUD7B and FZD4 were involved in the regulation of nuclear factor κB and Wnt/β-catenin signaling, respectively, and affected the viability of HCC cell lines. To evaluate the clinical significance of RA-responsive genes in HCC, gene expression analysis was performed using tumor and nontumor tissues from 171 patients. In univariate and multivariate analyses, low OTUD7B mRNA expression in tumor tissue was associated with a poor prognosis forHCC patients. Conclusion: We identified RA-responsive genes that exhibit antitumor activity against HCC cells. These findings provide useful information to understand the molecular mechanisms underlying the chemopreventive effects of RA against liver diseases, including HCC.
Citation Format: Goshi Shiota, Keita Kanki. Prognostic significance of the expression levels of target genes of retinoic acid in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 100A. doi:10.1158/1538-7445.AM2013-100A
Abstract 1010: New thiol-ω(γ-lactam amide) SAHA analogues as potent histone deacetylase (HDAC) inhibitors..
Authors: Giannini Giuseppe , Battistuzzi Gianfranco , Vignola Davide , Vesci Loredana , Milazzo Ferdinando Maria , Guglielmi Mario Berardino , Barbarino Marcella , Pisano Claudio , Cabri Walter 
Published: August 2014

Abstract
Histone deacetylase inhibitors (HDACi) are one of the last frontiers in pharmaceutical research. Two HDACi are already part of armamentarium of the anticancer drugs of the oncologists: Vorinostat, Zolinza® (SAHA) and Romidepsin, Istodax® (depsipeptide; FK-228), both licensed by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Beyond them, more than twenty new drugs are currently under pre-clinical and clinical investigation as single agent and in combination therapies against different cancers and in other several novel therapeutic indications. Mainly they are hydroxamic acids and benzamide derivatives; however none has emerged superior to SAHA in terms of potency.
In our search, we have selected a new generation of HDACi: thiol-based SAHA bearing a lactam amide in ω-position. This new generation was highly competitive compared to competing drugs, displaying sub-micromolar to low nanomolar inhibitor activity on HDACs, being especially powerful on HDAC6 isoform. They exhibited higher anti-proliferative activity than SAHA on different human cell lines. In vivo they were orally administered and showed a higher potency than SAHA, with a negligible toxicity.
The overall profile of this new class of HDAC inhibitors, including synthesis and a comprehensive pharmacological characterization, will be presented.
These encouraging results prompted us to select a drug candidate which is currently in a phase of pre-clinical evaluation.
Citation Format: Giuseppe Giannini, Gianfranco Battistuzzi, Davide Vignola, Loredana Vesci, Ferdinando Maria Milazzo, Mario Berardino Guglielmi, Marcella Barbarino, Claudio Pisano, Walter Cabri. New thiol-ω(γ-lactam amide) SAHA analogues as potent histone deacetylase (HDAC) inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1010. doi:10.1158/1538-7445.AM2013-1010
Abstract 1018: Inhibition of BET bromodomain targets genetically diverse glioblastoma.
Authors: Wang Jialiang , Cheng Zhixiang 
Published: August 2014

Abstract
Epigenetic regulations have been increasingly recognized as an integral part of tumor biology and attractive therapeutic targets. The bromodomain and extra-terminal domain (BET) proteins specifically recognize acetylated lysine residues on histone tails. BET bromodomain inhibition with a first-in-class inhibitor JQ1 reduces expression of a broad spectrum of growth promoting and antiapoptotic genes, including c-Myc, resulting in suppression of several hematopoietic cancers and NUT midline carcinoma. We and other groups have previously reported the critical role of c-Myc in glioblastoma stem cells. Here, we demonstrated broad antineoplastic effects of JQ1 both in ex vivo cultures and orthotopic models using a panel of glioblastoma tumors carrying different genetic lesions. JQ1 induced marked cell cycle arrest and apoptosis in association with p21WIP1/CIP1 induction and hTERT, Bcl-2 and Bcl-xL reduction. Consistent with previous studies, JQ1 decreased c-Myc expression in glioblastoma. However, exogenous c-Myc did not significantly protect glioblastoma from JQ1, unlike the observations in hematopoietic cancers. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these signaling pathways commonly altered in glioblastoma may not confer resistance to JQ1. Taken together, our results suggest potentially broad therapeutic utility of BET bromodomain inhibition for treating genetically diverse glioblastoma tumors.
Citation Format: Jialiang Wang, Zhixiang Cheng. Inhibition of BET bromodomain targets genetically diverse glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1018. doi:10.1158/1538-7445.AM2013-1018