bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1841: Selective inhibitors of nuclear export (SINE) activate multiple tumor suppressor pathways and kill prostate cancer cells across multiple genotypes in vitro and in vivo
Authors: Gravina Giovanni Luca , Ricevuto Enrico , Mancini Andrea , Shechter Sharon , Sandanayaka Vincent , Kauffman Michael G. , Shacham Sharon , Festuccia Claudio 
Published: August 2012

Abstract
CRM1 (Xpo1) is a key nuclear export protein which controls the nuclear export of multiple tumor suppressor proteins (TSP) and cell proliferation pathways including p53, p21, FOXO, PI3K/AKT, Wnt/ß-catenin and NF-κB. Mislocalization of TSP can abrogate their functions as well as render chemotherapies ineffective. Induction of nuclear expression of TSP and chemotherapy targets, by CRM1 inhibition can restore their tumor suppressor functions and increase drug sensitivity. We have developed orally active, small molecule SINE that irreversibly and potently inhibit CRM1 mediated nuclear export of multiple TSP and other cargoes (IC50 &lt; 100 nM). Here, we describe in vitro results using SINE compounds, KPT-185 in vitro and KPT-251 in vitro and in vivo on seven prostate cancer (PrCa) cell lines representing distinct differentiation/progression states of disease and genotypes: LAPC-4 (Androgen receptor [AR] positive, androgen dependent with low Akt/mTOR activities, p53 wt); LnCaP (AR positive, androgen dependent with high Akt/mTOR activities, p53 wt); LnCaP-C81 and LnCaP-C4-2B (AR positive, androgen independent with high Akt/mTOR activities, p53 wt); 22rv1 (AR positive, androgen independent with low Akt/mTOR activities, p53 wt); PC3 (AR negative, with high Akt/mTOR activites and no p53 function (p53 del) and DU145 (AR negative, with low Akt/mTOR activites and mutant p53). Benign prostatic hyperplasia line (BPH1) and Prostatic epithelial line (EPN) were used as non-neoplastic controls. We show that SINE block CRM1 mediated nuclear export of FOXO and p53 with a IC50 values &lt;100 nM in both PrCa and non-neoplastic cell lines. KPT compounds are selectively cytotoxic to PrCa lines with EC50s between 10 and 1000 nM, and show limited cytotoxicity on the non-neoplastic EPN and BPH1 lines (EC50 &gt;5-20 μM). SINE cytotoxic effects are independent of p53 status, and induce caspase-3 activation. SINE display synergistic effects in combination with cisplatin and docetaxel in vitro with combination indices between 0.3 and 0.8. In vivo results indicate that KPT-251 show a dose-dependent inhibition of tumor growth. KPT251 was also synergistic when administered at 30mg/kg/5 days/week per os with docetaxel and cisplatin by using the aggressive p53 wt 22rv1 xenografts. Taken together, CRM1 inhibition represents a completely novel, neoplasia-selective and well- tolerated target for use as single agent or in combination with chemotherapy for PrCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1841. doi:1538-7445.AM2012-1841
Abstract 1849: Identification and functional analysis of SHISA2 overexpressed in prostate cancer
Authors: Tamura Kenji , Furihata Mutsuo , Satake Hirofumi , Anchi Takashi , Kamei Maiko , Fukuhara Hideo , Shimamoto Tsutomu , Ashida Shingo , Karashima Takashi , Yamasaki Ichiro , Nishikawa Hiroshi , Kamada Masayuki , Yasuda Masaharu , Inoue Keiji , Shuin Taro 
Published: August 2012

Abstract
Prostate cancer (PC) is usually androgen-dependent and responds well to androgen ablation therapy. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype. These cancer cells are originally high-grade and show very poor response to any anticancer therapies. To identify novel molecular cancer drug targets, we previously analyzed the gene expression profiles of high-grade PCs using a cDNA microarray combined with laser microbeam microdissection and found a number of genes that are transactivated in high-grade PC. Among them, we report the identification of a novel molecular target, SHISA2. We confirmed overexpression of SHISA2 in high-grade prostate cancer cells by semi-quantitative RT-PCR and immunohistochemical analysis. Knockdown of SHISA2 expression by siRNA in a prostate cancer cell line resulted in a drastic decrease of cell numbers. In contrast, SHISA2 overexpression in a prostate cancer cell line promoted cell proliferation. These findings suggest that SHISA2 could be involved in aggressive phenotype of prostate cancers, including castration-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1849. doi:1538-7445.AM2012-1849
Abstract 1862: NY-ESO-1 and clinicopathological features in ovarian cancer
Authors: Topka Charlotte R. , ElMasri Wafic M. , Magyar Clara E. , Song Min , Dorigo Oliver 
Published: August 2012

Abstract
Ovarian cancer ranks fifth in cancer deaths among women and the American Cancer Society estimates that in the US about 15,460 women will die from this disease in 2011. NY-ESO-1 is an 18 kDa member of the cancer/testis 6 antigen family which is thought to play a role in germ cell differentiation. In healthy adults, NY-ESO-1 is restricted to the testis. NY-ESO-1 expression has been found in various malignant neoplasms, including melanomas, neuroblastomas, soft tissue sarcomas, and carcinomas from the breast and endometrium. To further delineate the role of NY-ESO-1 in epithelial ovarian cancer, we constructed a tissue microarray of archived formalin-fixed paraffin-embedded paired tumor and normal control specimens from ovarian cancer patients. NY-ESO-1 expression was correlated with clinicopathologic features and overall survival. Specimens were collected from 242 patients who underwent cytoreductive surgery for ovarian cancer between 1989 and 2009. Immunohistochemical staining was performed with mouse monoclonal antibody clone E978 specific for NY-ESO-1. Stained slides were digitized with the Aperio ScanScope XT and images were analyzed using DEFINENS Tissue Studio software. Histological scores (H-scores) based on intensity of NY-ESO-1 staining and percent positive cells were calculated for all specimens. Positive NY-ESO-1 expression was found in 21% of papillary serous carcinomas, 18% of endometrioid carcinomas, and 20% of clear cell carcinomas. Ovarian cancer tissue had significantly higher H-scores compared to normal tissue controls from the same patients. H-scores increased with increasing FIGO stage and grade of the tumors. Caucasians had higher H-scores compared to African Americans and Asians. H-scores did not correlate with overall survival. Similarly, no differences in overall survival based on NY-ESO-1 expression levels were detected when patients were stratified by their histologic subtype. In conclusion, NY-ESO-1 is expressed in all histologic subtypes of epithelial ovarian cancer but not in normal tissues, therefore making it an ideal candidate for the development of targeted therapeutic approaches in ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1862. doi:1538-7445.AM2012-1862
Abstract 1864: Role of store-operated Ca2+ entry in proliferation and cell cycle in melanoma
Authors: Umemura Masanari , Baljinnyam Erdene , De Lorenzo Mariana S. , Feske Stefan , Xie Lai-Hua , Iwatsubo Kousaku 
Published: August 2012

Abstract
Background: Melanoma has a poor prognosis due to its rapid progression and a high metastatic ability. Ca2+ homeostasis plays a pivotal role in proliferation in cancer cells, but little is known about the role of Ca2+ in melanoma. Store-operated calcium entry (SOCE) is defined as Ca2+ entry from extracellular space triggered when Ca2+ store in the endoplasmic reticulum (ER) is depleted. SOCE is regulated by coordination between Orai (ORAI calcium release-activated calcium modulator) in the plasma membrane, and STIM1 (stromal interaction molecule 1) in the ER. We examined the role of Ca2+ in melanoma cells especially focusing on SOCE. Method: Intracellular Ca2+ level was measured by using Fluo4-AM, a Ca2+-sensing fluorescent dye. Cell proliferation was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cells were stained with propidium iodide and cell cycle was assessed using flow cytometer. Protein phosphorylation microarray was performed by using a commercially available kit (Cancer Signaling Phospho-Antibody Array). Results: SOCE, as demonstrated by enhancement of Ca2+ entry from extracellular space after Ca2+ depletion in the ER, was observed in SK-MEL-2, C8161, SK-MEL-24, UACC257 (human) and B16 (mouse) melanoma cell lines, suggesting that the existence of SOCE is universal among melanoma cells. SOCE was attenuated by Pyr3, a pyrazole compound which is known to inhibit SOCE, as well as by EGTA that chelates extracellular Ca2+. Pyr3 inhibits cellular proliferation in SK-MEL-2 cells (IC50: 5.1uM) and C8161 cells (IC50: 2.1uM). Cell cycle was analyzed in C8161 cells, and the cell number in the G2 phase was increased by both Pyr3 and EGTA, indicating that SOCE plays a role in the transition of G2/S phase. Protein microarray data showed that Pyr3 reduces phosphorylation of signal transducers and activators of transcription 5 (STAT5) by 93%, suggesting that the JAK/STAT pathway may be involved in SOCE-induced alteration of cell cycle. Conclusion: Our results showed that inhibition of SOCE suppresses proliferation in melanoma, thus it could be a new strategy for melanoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1864. doi:1538-7445.AM2012-1864
Abstract 1877: Predictive marker discovery for Sorafenib using patient derived xenograft models of hepatocellular carcinoma
Authors: Zhang Juan , Sun Yanmei , Song Xiaoming , Yang Jie , Cai Jie , Shi Qian , Chen Taiping 
Published: August 2012

Abstract
Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)- mediated angiogenesis and blocking the RAF/extracellular signal regulated kinase (ERK) kinase (MEK)/ERK cascade, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). Although it is only used in treating advanced renal cell carcinoma and unresectable HCC, many patients with other malignant diseases as well as patient with resectable HCC may also benefit from this treatment. There is a clear need for predictive markers of Sorafenib to help selecting the patient population that may benefit the most. We set out to discover the predictive markers using patient derived xenograft (PDX) models of HCC. The response to Sorafenib was investigated in 20 PDX subcutaneous models and 6 orthotopic cell line (MHCC97H, HUH-1, HepG2, Hep3B, SK-Hep-1 and PLC/PRF/5) derived xenogrft (CDX) models. 11 out of 20 PDX models (55%), and 4 out of 6 CDX models (67%) achieved significant tumor growth inhibition by the treatment of Sorafenib at the dose range from 25-50 mg/kg in nude mice. Gene expression profile, hotspot mutation detection and copy number variations were analyzed to sift out the molecular signatures that may be predictive of the response to Sorafenib. Genes and pathways such as VEGF, PDGF, FGF, Raf/MAPK/ERK, PTEN/ PI3K/AKT/mTOR, TGF-beta/Wnt, EGFR, IGF and HGF/c-MET, were investigated using methods such as IHC analysis of pretreatment xenograft tissues. Our results indicate that more than half of the resectable HCC may be responsive to Sorafenib treatment, and markers other than the usual targets of Sorafenib may be predictive of this response. This study may shed light on the predictive markers of Sorafenib and help patients that may be mostly benefited from this drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1877. doi:1538-7445.AM2012-1877
Abstract 1878: Upregulation of UGT1A4 by fulvestrant: A potential elimination mechanism of anastrazole in breast cancer treatment
Authors: Edavana Vineetha Koroth , Dhakal Ishwori B. , Williams Suzanne , Kadlubar Susan A. 
Published: August 2012

Abstract
The pure antiestrogen, fulvestrant (Faslodex®) has been approved for use in the treatment of postmenopausal patients with hormone-receptor positive metastatic disease. It has been postulated that the combination of an aromatase inhibitor with a pure antiestrogen could provide therapeutic advantages over the administration of an aromatase inhibitor alone. The effect of co-administration of these drugs on Phase I and Phase II metabolism (i.e. glucuronidation) have not been explored. The role of pharmacogenetics in clinical benefit and overall survival in patients receiving anastrozole and fulvestrant is unexplored. In this study, we demonstrated that fulvestrant up-regulates expression of UDP glucuronosyltransferase (UGT) 1A, the major enzyme responsible for the direct conjugation and subsequent elimination anastrozole. Endogenous mRNA expression levels of UGT1A4 in HepG2 cells were induced 4.2-fold by fulvestrant treatment in the ERα-expressing cell line. In vitro assays using liver microsomal specimens from individual subjects demonstrated 163 fold variability in anastrazole glucuronidation. Anastrazole glucuronodation was correlated (r = 0.977, p &lt;0.0001) with lamotrigine glucuronidation, a diagnostic substrate for UGT1A4. We also found a significant correlation between anastrazole glucuronidation and UGT1A4 mRNA expression levels in these HLMs (r = 0.978, p &lt;0.0001). We also examined whether UGT1A4 promoter SNPs were associated with the observed interindividual variability in anastrozole glucuronidation. Microsomes from the subjects with mutated heterozygous UGT1A4 promoter SNPs 36G&lt;A and SNPs 217 T&lt;G exhibited a significantly higher activity than the microsomes from the subjects with homozygous wild type UGT1A4 promoter SNP 36G&lt;A and SNP 217 T&lt;G. On the other hand, microsomes from the subjects with homozygous wild typeUGT1A4 promoter SNPs 219C&lt;T and SNPs 163G&lt;A exhibited significantly higher activity when compared with microsomes from the subjects with mutated heterozygous UGT1A4 promoter SNPs 219C&lt;T and SNPs 163G&lt;A. These in vitro studies indicate that fulvestrant administration could influence the disposition of anastrazole in combination therapy of aromatase inhibitor with a pure antiestrogen by up regulating the phase II metabolizing enzyme UGT1A4. Our data also suggest that the UGT1A4 promoter polymorphisms may be associated with altered rates glucuronidation and detoxification of anastrazole in vivo. Further studies are needed to assess the complete effects of fulvestrant administration on the disposition of drugs that are substrates of UGT1A4.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1878. doi:1538-7445.AM2012-1878
Abstract 1880: Incorporating protein levels with genetic variation and gene expression in sensitivity to chemotherapy
Authors: Stark Amy L. , Hause Ronald J. , Gorsic Lidija K. , Antao Nirav N. , Chung Sophie H. , Gill Daniel F. , White Kevin P. , Jones Richard B. , Dolan M. Eileen 
Published: August 2012

Abstract
Genome-wide studies of genes important in chemotherapeutic sensitivity or disease susceptibility and progression have primarily relied on mRNA expression levels; however, mRNA expression levels do not always accurately reflect downstream protein abundances. We have applied a novel technology, microwestern arrays, along with reverse phase lysate arrays, to evaluate the role that over 400 transcription factor and signaling proteins play in mediating cellular sensitivity to ten chemotherapeutic agents. Utilizing unrelated International HapMap lymphoblastoid cell lines derived from the Yoruba population, we evaluated the relationship between protein abundances, genetic variation, microRNA and mRNA expression, and chemotherapeutic-induced cytotoxicity and apoptosis. Using ∼12 million single nucleotide polymorphism (SNPs) imputed from the 1000 Genomes Project, we identified SNPs associated with protein abundance (protein quantitative trait loci, pQTLs) and SNPs associated with chemotherapeutic sensitivity (drug quantitative trait loci, dQTLs). Chemotherapeutic agents included platinating agents, antimetabolites and microtubule inhibitors. For cytarabine there was a significant (p&lt;0.0001) enrichment of pQTLs in the SNPs associated with cytotoxicity and apoptosis. We also identified 71 protein levels associated with cytarabine-induced cytotoxicity and apoptosis at p&lt;0.05. One protein, ATF2, was associated (p&lt;0.006) with both high (40 µM) and low (5 µM) dose cytarabine-induced apoptosis and there were six SNPs associated with apoptosis phenotypes (p&lt;0.00007) that also associated with the protein level (p&lt;0.00009). Knockdown of ATF2 protein with siRNA resulted in 40-51% of endogenous levels concomitant with a significant increase in apoptosis induced by cytarabine at both doses (p=0.001). This relationship was not identified in analyses correlating mRNA with phenotypes thus demonstrating the importance of incorporating protein levels into studies that aim to identify potential biomarkers. By incorporating genetic variation, mRNA, protein, and microRNA levels with chemotherapeutic sensitivity, the complex role of the genetic architecture in cellular chemotherapy response through its effects on expression and protein can be better understood. This study has broad potential for application to other chemotherapeutic drugs and complex traits.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1880. doi:1538-7445.AM2012-1880
Abstract 1882: Gemcitabine pathway SNPs are associated with its PK parameters in patients with solid tumors
Authors: Mitra Amit K. , Khatri Amit , Kirstein Mark N. , Kratzke Robert A. , Lamba Jatinder K. 
Published: August 2012

Abstract
Gemcitabine (2′, 2′-difluoro 2′-deoxycytidine, dFdC) is a cytotoxic pyrimidine antimetabolite used as first-line chemotherapeutic agent for the treatment of a wide range of solid tumors and hematologic malignancies. It is as a pro-drug that undergoes cellular uptake through transporters like human equilibrative nucleoside transporter (hENT1/SLC29A1) and human concentrative nucleoside transporters (hCNT1/SLC28A1 and hCNT3/SLC28A3) followed by extensive intracellular phosphorylation by kinases like deoxycytidine kinase (DCK) and cytidine monophosphate kinase (CMPK) to its active diphosphorylated (dFdCDP) and triphosphorylated (dFdCTP) forms. Gemcitabine is primarily inactivated via deamination to its less potent metabolite 2′, 2′-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA). High inter-patient variability in response to gemcitabine treatment has been a major concern in gemcitabine chemotherapy. However, association of pharmacogenomics with gemcitabine pharmacokinetics (PK) has not been extensively studied so far. In the present study, therefore, we investigated association between single nucleotide polymorphisms (SNPs) within genes involved in gemcitabine transport/metabolic pathway and pharmacokinetic parameter estimates for gemcitabine and metabolites in patients diagnosed with solid tumors. Pharmacokinetic blood sampling (n=40) was as follows: pre-infusion, 5, 15, 30, 45 min, and 1, 1.25, 1.5, 2, 6, 24, 48 and 72 hours after the end of gemcitabine infusion. Gemcitabine and dFdU concentrations in plasma and intracellular dFdCTP levels in PBMCs were measured using HPLC-UV and LC MS/MS. A total of 86 SNPs in 14 genes viz. CDA, CMPK, CTPS, DCK, DCTD, NME1, NME2, NME3, NME4, NT5C2, NT5C3, SLC28A1, SLC28A3, and SLC29A1 were genotyped using Sequenom-based assays. Pharmacogenomic association was evaluated using Wilcoxon rank-sum test and Kruskal-Wallis one-way analysis of variance by ranks (p≤0.05). SNPs in 5′ nucleotidase genes- rs1163075, rs1926029, rs11598702 and rs1712517 in NT5C2 and rs3750117 in NT5C3 were associated with gemcitabine elimination clearance. SNPs in CDA- rs1048977 and rs4655226 were associated with dFdU clearance. SNPs in CTPS- rs4430318, rs61780437 and rs1044457 were strongly associated with higher dFdCTP formation clearance. Additionally, CDA, DCTD, SLC28A1, SLC28A3 and SLC29A1 SNPs were also associated with dFdCTP formation clearance. The results from our study indicate pharmacogenomic association between gemcitabine pharmacokinetic pathway SNPs and PK parameters. Presence of these SNPs could impact outcomes for patients receiving gemcitabine therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1882. doi:1538-7445.AM2012-1882