bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2783: A novel functional variant is associated with regulation of the prostate stem cell antigen (PSCA) gene and bladder cancer risk in males
Authors: Fu Yi-Ping , Kohaar Indu , Muchmore Brian , Mumy Adam , Tang Wei , Porter-Gill Patricia , Garcia-Closas Montserrat , Chanock Stephen , Figueroa Jonine , Baris Dalsu , Purdue Mark , Thun Michael , Albanes Demetrius , Malats Nuria , Real Francisco X. , Kogevinas Manolis , Johnson Alison , Schwenn Molly , Rothman Nathaniel , Silverman Debra , Prokunina-Olsson Ludmila 
Published: June 2012

Abstract
Genome-wide association studies (GWAS) identified allele T of SNP rs2294008 within the prostate stem cell antigen (PSCA) gene as a risk factor for diffuse gastric cancer (OR=1.67, p=2.2×10-15) (The Study Group of Millennium Genome Project for Cancer, Nat Genet, 2008) and bladder cancer (OR=1.13, p=4.4×10-11) (Rothman et al, Nat Genet, 2010). In the present study we used data from the Stage 1 bladder cancer GWAS, which was performed on 8,801 individuals of European ancestry (3,529 cases and 5,115 controls), and information from the 1000 Genomes and HapMap 3 projects to impute all other SNPs within +/- 50kb region surrounding PSCA. Association analysis on the combined set of all genotyped and imputed SNPs (n=375) revealed a novel bladder cancer association signal for a variant genotyped in all samples. The association was found only in males (n=7,359, crude OR =1.14, p=1.15×10-4; adjusted for all covariates and rs2294008, OR=1.13, p=1.32×10-3), while no association was observed in females (n=1,442, crude OR=0.98, p=0.81; adjusted for all covariates and rs2294008, OR=0.98, p=0.82). The low linkage disequilibrium between these two SNPs (D’=0.202 and r2=0.019 in 8801 GWAS samples) suggests these variants are independent. A joint analysis showed that these two SNPs have a compound association with bladder cancer dependent on the number of risk genotypes (0, 1 or 2) in males (adjOR=1.18, p=3.93×10-6) but not in females (adjOR=1.01, p=0.95).
The risk allele T of rs2294008 is functional as it introduces a novel translation start site that creates a PSCA protein with a leader peptide extended by 11 amino acids. The novel SNP that was found 10 Kb upstream of rs2294008, lies within an alternative untranslated first exon of PSCA that is marked by a H3K4me3 signal and is in a vicinity of an androgen receptor binding site, suggesting a possible role for this variant in regulation of PSCA promoter activity. In conclusion, a novel independent functional variant associated with bladder cancer risk was found within the PSCA gene, which might be important for male-specific regulation of PSCA expression and carcinogenesis.
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 2783. doi:10.1158/1538-7445.AM2011-2783
Abstract 2786: Identification and preclinical characterization of EMD 1204831 – A selective c-Met kinase inhibitor in clinical phase 1
Authors: Bladt Friedhelm , Blaukat Andree , Dorsch Dieter , Fittschen Claus , Friese-Hamim Manja , Graedler Ulrich , Knuehl Christine , Meyring Michael , Schadt Oliver , Stieber Frank 
Published: June 2012

Abstract
The involvement of the mesenchymal endothelial transition factor (c-Met) in the primary event of oncogenic transformation and the secondary ability to mediate metastatic spread has been convincingly demonstrated in preclinical and early clinical settings. The clinical benefits of c-Met kinase inhibitors with various modes of actions and selectivity profiles are currently under investigation hoping that inhibitors of c-Met might emerge as valuable cancer therapeutics in the future. During an HTS run 3-(diethylamino)propyl N-[3-[[5-(3,4-dimethoxyphenyl)-2-oxo-6H-1,3,4-thiadiazin-3-yl]methyl]phenyl]carbamate was identified as an attractive lead structure with an interesting overall profile (clogD (7.4): 2.5, S (pH 7.4): &gt;100 µg/ml, IC50 (cMet enzyme): 30 nM, IC50 (cMet A549): 800 nM) providing a valid starting point. The co-crystal structure of 1 revealed the binding mode and the essential structural features. The initial HTS hit was bound in a DFG-in conformation interacting with the main chain nitrogen atom of Met1160 within the hinge region and with the main chain nitrogen of Asp1222. After subsequent optimization of potency, efficacy, PK properties and the safety profile of thiadiazinone 1, EMD1204831 was identified as development compound. EMD1204831 is currently being investigated in a phase 1 clinical trial. The pyridazinone EMD1204831 inhibits enzymatic and cellular c-Met kinase activity with IC50 values of 12 nM and 15 nM, respectively. EMD1204831 displayed an exquisite selectivity when tested in vitro against a panel of more than 400 potential off-targets, including kinases, GPCRs, ion channels, transporters and various enzymes. EMD 1204831 demonstrated excellent anti-tumor activity in vivo in a variety of xenograft models, including U87-MG glioblastoma cells (autocrine HGF expression), TPR-Met-transformed mouse fibroblasts (oncogenic Met fusion protein) or Hs746T gastric cancer cells (c-Met gene amplification and HGF-independent activation). Depending on the particular model, complete regressions were observed with doses as low as 6 mg/kg/d administered per os. PK/PD analysis revealed efficient, dose- and time-dependent inhibition of c-Met phosphorylation, reduction of IL-8 and cyclin D1 expression as well as an induction of the cell cycle inhibitor p27. The overall profile of EMD1204831 including first time structural disclosure, some structure activity relationships, in vitro potency, selectivity profile and in-vivo data will be presented.
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 2786. doi:10.1158/1538-7445.AM2011-2786
Abstract 2787: Discovery of GDC-0980, a selective PI3K/mTOR inhibitor in clinical trials
Authors: Sutherlin Daniel P. , Belvin Marcia , Bao Linda , Berry Leanne , Berry Megan , Castanedo Georgette , Edgar Kyle , Folkes Adrian , Friedman Lori , Heffron Tim , Patel Sonal , Olivero Alan , Lesnick John , Lewis Cristina , Marsters James , Nonomiya Jim , Pang Jodie , Prior Wei Wei , Salphati Laurent , Sampath Deepak , Tsui Vickie , Wallin Jeff , Wei BinQing , Weismann Christian , Zhu Bing-Yan 
Published: June 2012

Abstract
PI3 Kinase and mTOR have been identified as promising targets for the treatment of cancer. These enzymes participate in related, but not redundant, signaling networks to transmit cellular growth and survival signals, which are hallmarks of tumor growth. An interest in targeting both of these two important points along this critical signaling pathway, and the ability to leverage the high degree of structural similarity in the active sites of PI3K and mTOR kinase, has resulted in the discovery of GDC-0980 as a Class I PI3K and mTOR kinase inhibitor for oncology indications. The structure, efficacy, and medicinal chemistry behind the discovery of this compound is described.
Beginning with the morpholin-4-yl-thieno[3,2-d]pyrimidine core of the Class I PI3K inhibitor GDC-0941, structural substitutions were made external to the core that added mTOR potency, improved the metabolic stability in vitro and in vivo, and lowered the plasma protein binding of the scaffold. Homology models of mTOR using PI3Kγ structures with bound inhibitors provided hypotheses for increasing mTOR potency relative to previous compounds. The solubility of the modified compounds was improved through the addition of polar functionality in the solvent exposed region of the scaffold, resulting in GDC-0980.
GDC-0980 is potent across Class I isoforms with IC50's of 5, 27, 7, and 14 nM for PI3Kα, β, Δ, and γ, and inhibits mTOR with a Ki of 17 nM. The compound is highly selective versus a large panel of kinases including others in the PIK family. Based on the excellent PK profile, linear increase in exposure, strong potency in a broad range of cancer cells, and high free fraction, GDC-0980 is efficacious in animal models of cancer when dosed orally at low doses. Furthermore, this compound is efficacious when dosed intermittently as well as on a daily schedule. These preclinical data provide compelling support for GDC-0980 as a clinical candidate, and early stage clinical trials are underway.
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 2787. doi:10.1158/1538-7445.AM2011-2787
Abstract 279: Use of GFP-STAT3βtc for EMSA analysis of protein-protein and protein-DNA interactions in tumorigenic signalling pathways
Authors: Wilderspin Andrew F. , Nkansah Edwin , Zinzalla Giovanna , Stephenson F. Anne , Thurston David E. 
Published: June 2012

Abstract
STAT3 (Signal transducer and activator of transcription 3) is a homodimeric transcription factor that binds to the response element of a number of genes that promote tumorigenesis when over-expressed. Tumorigenesis, in many cases, correlates with an aberrant signalling cascade that leads to uncontrolled activation of STAT3. Activation is widely understood to be a result of phosphorylation at tyrosine 705 which leads to dimerisation and DNA binding.
We have investigated the dimerisation and DNA binding of STAT3βtc in an isolated cell-free system in order to understand the conditions which modulate these interactions, and to facilitate the discovery of small molecules capable of interfering with these interactions. We designed a GFP-STAT3βtc construct in which the N-terminal 126 amino acids of STAT3 were replaced with spectral variants of the GFP (green fluorescent protein) to act as a reporter. The constructs also lacked the unstructured C-terminal activation domain of STAT3 to avoid aggregation of the purified protein. Phosphorylated and non-phosphorylated GFP-STAT3βtc proteins were purified from BL21(DE3)TKB1 and Rosetta strains of E. Coli, respectively. Soluble expression was observed when tagged with GFP at the N-terminus but not the C-terminus.
Using both conventional ELISA and fluorescence-based microtiter plate assays, we demonstrated that both active (phosphorylated) and inactive (non-phosphorylated) fluorescent STAT3βtc can bind to immobilised dsDNA (M67; a modified c-fos sis inducible enhancer) or an immobilised surrogate receptor (a phosphotyrosyl peptide derived from the interleukin-6 receptor subunit gp130), respectively. Furthermore, we were able to demonstrate disruption of a pre-formed non-phosphorylated GFP-STAT3βtc/DNA complex with a phosphotyrosyl peptide at an IC50 of 30 µM. In contrast, 500 µM peptide appeared to have no effect on phosphorylated GFP-STAT3βtc bound to M67.
In summary, we have developed an EMSA assay for the STAT3/STAT3 transcription factor based on a protein mobility shift rather than a DNA mobility shift, and which utilizes fluorescent tagged STATs. Both non-phosphorylated and phosphorylated fluorescent STAT3 proteins form a stable complex with M67 DNA, but only the non-phosphorylated STAT3/DNA complex can be disrupted with a phosphotyrosyl peptide in the EMSA assay. This assay is now being utilized for the discovery of novel small molecule inhibitors of the STAT3/STAT3 interaction.
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 279. doi:10.1158/1538-7445.AM2011-279
Abstract 2804: Increased metastasis linked to defective mitochondria and elevated ROS in BNip3 deficient mammary tumorigenesis
Authors: Tracy Kristin , Chen Hong , Barth Sandra , Macleod Kay F. 
Published: June 2012

Abstract
BNIP3 is a hypoxia-inducible mitochondrial protein that has been implicated in mitochondrial fragmentation and subsequent mitophagy. BNIP3 protein has also been shown to be up-regulated at pre-malignant stages of various different human cancers, including breast cancer and down-regulated later through a variety of mechanisms, including promoter methylation and altered sub-cellular localization. With an established role for hypoxia in promoting invasiveness and progression to metastasis in breast cancer, we were interested to determine how BNIP3 (as a HIF target gene) acted in tumor progression. To do this, we crossed mice carrying a targeted deletion in the mouse BNip3 gene to the MMTV-PyMT mouse model of breast cancer. All analyses were performed on mice backcrossed onto a pure FVB/N genetic background. We show that while loss of BNip3 has only a modest effect on primary tumor growth, there is a highly significant increase in the numbers of lung metastases and a reduced latency to metastasis in the MMTV-PyMTl;BNip3-/- mice compared to control MMTV-PyMT;BNip3+/+ mice. BNip3 null tumors showed increased invasive properties and nuclear grade at earlier stages that were transplantable to wild-type host mice arguing that the phenotype was cell-intrinsic to BNip3 null tumor cells. This invasive pathology was also associated with increased tumor cell proliferation, increased HIF-1α levels, increased CD31-positive blood vessel formation and elevated MMPase activity. BNip3 null tumor cells exhibited abnormal mitochondria, reduced mitochondrial membrane potential and increased ROS levels. In vitro, quenching ROS limited the increased invasion/migration properties of BNip3 null tumor cells under hypoxia. These results suggest that BNip3 is a metastasis suppressor by virtue of its role in maintaining mitochondrial integrity that mitigates against the metastasis promoting activity of hypoxia.
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 2804. doi:10.1158/1538-7445.AM2011-2804
Abstract 2824: PENAO: A small molecule tumor metabolism inhibitor
Authors: Dilda Pierre J. , Decollogne Stephanie , Weerakoon Lakmini , Hogg Philip J. 
Published: June 2012

Abstract
Tumors reorganize the metabolic steps used by normal tissues for glucose utilization and ATP production. Normal tissues rely heavily on oxidative phosphorylation for ATP, while tumor cells employ a route that includes a much greater dependency on glycolysis. This aberrant metabolism allows for tumor survival when oxygen is limiting while providing a mechanism to poison the extracellular environment with acid, which facilitates invasion and metastasis.
In particular, tumors harness a crucial enzyme, hexokinase II (HKII), to entrap and channel glucose toward glycolysis. HKII is bound to mitochondria via interaction with the voltage dependent anion channel (VDAC). This affords HKII preferential access to the mitochondrial ATP via inner-membrane adenine nucleotide translocase (ANT) to rapidly phosphorylate and trap the incoming glucose, effectively initiating and regulating the glycolytic flux across the tumor cytosol.
We have developed a novel covalent inhibitor of ANT called PENAO, (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) (1). This molecule blocks ANT delivery of ATP to VDAC-bound HKII, thus inhibiting tumor cell metabolism, and triggers the mitochondrial permeability transition pore, resulting in proliferation arrest and apoptotic cell death. PENAO rapidly enters the cell via an organic ion transporter and reacts with Cys160 and Cys257 on the matrix face of ANT, which leads to arrest of proliferation of the cell and then apoptosis. PENAO targets both proliferating endothelial and tumor cells. It is very well tolerated in mice and has potent anti-tumor activity in murine tumor models when administered either subcutaneously or intravenously.
PENAO is the most potent anti-tumor compound of its type so far reported and will enter a Phase I/IIa clinical trial in adults with solid tumors refractory to standard therapy in 2011.
1. Dilda PJ, Decollogne S, Weerakoon L, et al. Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. J Med Chem 2009;52(20):6209-16.
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 2824. doi:10.1158/1538-7445.AM2011-2824
Abstract 283: Vascular ageing as a modulator of tumor angiogenesis, antiangiogenesis and metastasis
Authors: Meehan Brian , Kadlubowska Dorota , Dombrovsky Alexander , Rak Janusz W. 
Published: June 2012

Abstract
Ageing profoundly influences vascular homeostasis and impacts angiogenesis, including in cancer. This is rarely considered in preclinical studies, as mouse tumor models usually rely on animals between 1-6 months of age (5-25% of life expectancy), while the majority of adult cancer patients are diagnosed in later decades of life. Thus a better characterization of a pediatric, adult and geriatric state of the vascular system is badly needed to properly design age-appropriate antiangiogenic anticancer therapies.
Using aged (over 12 months old), aged and atherosclerotic (ApoE-/-) and aged and diet induced obese (DIO) C57BL/6 mice we have demonstrated that model tumors (Lewis Lung Carcinoma) exhibit profoundly different angiogenic and metastatic patterns in those settings then in conventional syngeneic recipients. We documented age-related molecular differences in tumor blood vessels and have shown that the antitumor effects of several therapeutic agents (L-NAME, Sutent, AG28262, metronomic cyclophosphamide) are affected by vascular age and comorbidities. Age also changes the pattern of metastasis as aged mice tend to exhibit less aggressive metastatic growth. On the other hand metastasis following treatment with antiangiogenic agents (Sutent without chemotherapy) is more accentuated in young mice then in their aged counterparts. Finally, we report age-related changes in vascular characteristics of human kidney tumours, including a significantly higher expression of eNOS in tumours of younger patients.
Overall, these observations suggest that age may play a significant role in modulation of angiogenesis, antiangiogenesis and metastasis in various tumor settings and agents more effective in adult patients may not have the same impact in the pediatric population.
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 283. doi:10.1158/1538-7445.AM2011-283
Abstract 2831: Novel antibody-drug conjugates for selective tumor activation
Authors: Setter Jocelyn R. , Doronina Svetlana O. , Bovee Tim D. , Anderson Marti E. , Senter Peter D. , Benjamin Dennis R. , Lyon Robert P. 
Published: June 2012

Abstract
Auristatin based antibody-drug conjugates (ADCs) have demonstrated profound activites, both preclinically and clinically. Upon internalization, the active auristatin is released through proteolytic degradation of the linker, where it induces cell kill through the inhibition of tubulin polymerization. Once released from the antibody, clearance of the auristatin proceeds via the hepatobiliary route. This finding prompted us to explore new auristatin-peptide drug linkers that had the capacity to release the active form of the drug in tumors, but an inactive form in the liver. To this end, we designed a novel in vivo screen in which multiple ADCs were cassette dosed in mice. LC-MS/MS was used to determine which sequences amongst approximately 800 new auristatin-peptide derivatives allowed for differential drug activation. Sequences were identified that allowed for more selective intratumoral release of the active drug.
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 2831. doi:10.1158/1538-7445.AM2011-2831
Abstract 2847: Host angiopoietin-2 inhibits tumor growth and angiogenesis in the liver
Authors: Im Jae Hong , Balathasan Lukxmi , Yameen Sabira , Tapmeier Thomas , Hill Sally , Bernhard Eric , Gorden D.Lee , Kruse Karoline , Augustin Hellmut , Muschel Ruth J. 
Published: June 2012

Abstract
For growth and survival in metastasis, tumor colonies must develop new intratumoral vasculature for supply of nutrients and oxygen. Since angiopoietin-2 (Ang2) resulted in a burst of angiogenesis in the glioma model, we examined the effects of host Ang2 on colony growth and neo-angiogenesis during the liver colonization.
Liver colonization was induced through the intrasplenic injection of MC38-GFP (murin colorectal carcinoma cells) into two genotype mice of the ang2−/− mice and the wild type mice. When colonies were established, the livers were isolated and analyzed using flow cytometry, immunoflorescent histochemistry and ELISA. In addition, the blood was collected from vena cava for measurement of MCP-1 at 14 days.
Flow cytometry analyses of whole livers showed that the tumor cell population in the ang2−/− mice was approximately 2 times larger than in the wild type mice. Immunoflorescent histochemistry of the liver tissue using antibodies for CD31, CD34, CD146, VE-cadherin and NG2 showed that intratumoral vascular density and vascular maturity in the ang2−/− mice were approximately 2 times higher than the wild type mice. Intratumoral vessels were significantly positive for CD146 and CD34, markers more frequently associated with neo-angiogenesis, but much less for CD31. There was no significant difference in VEGF level which is known to mediate vascular response in combination with Ang2. CD11b positive cells and MCP-1 concentration in the livers were equivalent in two genotypes. Notably, there were approximately 10 times more Tie2+/CD11b+ cells in the ang2−/− mice than the wild type mice. CD11c+/CD45+ cell populations were slightly different in two genotypes. These results suggested that host Ang2 would inhibit tumor growth and neo-angiogenesis in the liver, and that the inhibition is correlated with the decreased recruitment of TEMs, one of myeloid cells, into the liver.
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 2847. doi:10.1158/1538-7445.AM2011-2847