bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3063: Mcl-1 dependency is a predictive biomarker for apoptotic induction by short-term dinaciclib (SCH 727965) treatment
Authors: Booher Robert , Hirsch Heather , Strack Peter , Zawel Leigh , Fawell Stephen 
Published: August 2012

Abstract
Dinaciclib (SCH 727965) is a potent and selective inhibitor of the cyclin-dependent kinases (CDKs) 1, 2, 5 and 9 undergoing clinical testing against a range of solid and hematologic malignancies. From preclinical studies, more than 140 cell lines have been profiled for dinaciclib response in long-term (&gt;72 hrs) viability or clonogenicity assays with &gt;97% of the lines showing IC50 β25 nM. This uniformly low nM potency is likely due to repression of both cell cycle progression and transcription through inhibition of CDK1/2 and CDK9, respectively. CDK9 phosphorylation of the RNA pol II (RNAPII) at Ser2 and 5 is required for transcriptional initiation and elongation. We and others have observed rapid CDK9-dependent effects on cells after short-term dinaciclib exposure, including loss of RNAPII Ser2 phosphorylation followed by rapid elimination of the short half-life, pro-survival protein Mcl-1. Since a cancer cell's ability to avoid apoptosis is dependent on the balance of several Bcl-2 antiapoptotic family members, including Bcl-2, Bcl-xL and Mcl-1, we hypothesized that Mcl-1 dependent cell lines would be more sensitive to dinaciclib treatment. Moreover, we anticipated that this differential sensitivity could be discriminated from longer-term inhibitory cell cycle effects by conducting short-term dinaciclib exposure assays. Here we report the activity of dinaciclib to induce apoptosis on a panel of 25 human solid tumor cell lines with varying levels of Mcl-1 dependency. Mcl-1 dependency in solid tumor cell lines has been reported to correlate with the Mcl-1 to Bcl-xL mRNA ratio or the level of Mcl-1 gene amplification. Cell viability was assessed after an 18 hour, 100 nM dinaciclib treatment while target engagement and induction of apoptosis was determined after 8 hours. With one exception, all cell lines showed potent CDK9 target engagement as determined by loss of RNAPII Ser2 phosphorylation and corresponding reduced Mcl-1 protein levels. We observed that loss of cell viability, measured by ATP content, directly correlated with the Mcl-1/Bcl-xL mRNA ratio. A dramatic increase in PARP cleavage was also observed in cell lines with the highest Mcl-1/Bcl-xL mRNA ratio. Furthermore, the extent of PARP cleavage correlated with levels of caspase-3/7 activity. Bcl-2 levels did not significantly impact the dinaciclib response. These data provide a rationale for utilizing Mcl-1 dependency as a predictive biomarker for dinaciclib anti-cancer response in solid tumor malignancies.
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 3063. doi:1538-7445.AM2012-3063
Abstract 3116: Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in ovarian cancer
Authors: Timms Kirsten M. , Abkevich Victor , Hennessy Bryan T. , Potter Jennifer , Carey Mark S. , Meyer Larissa A. , Broaddus Russell , Lu Karen H. , Jammulapati Srikanth , FitzGerald Lisa , Krivak Thomas C. , DeLoia Julie A. , Gutin Alexander , Mills Gordon B. , Lanchbury Jerry 
Published: August 2012

Abstract
Introduction: BRCA1 and BRCA2 are key members of the homologous recombination (HR) pathway. Mutations in these genes and other HR pathway defects have potential therapeutic relevance when used to support agents that introduce or exploit double-strand DNA breaks. This study examines the association between HR deficiency and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumors from two independent datasets were characterized for germline and somatic defects in BRCA1 and BRCA2. Whole genome LOH profiles were generated using Affymetrix SNP arrays. Publically available data was downloaded from the TCGA website for a third independent ovarian cancer dataset. RAD51C promoter methylation was assayed in two of the datasets. Comprehensive profiling of BRCA1 and BRCA2 defects, and genome wide LOH was also performed on approximately 70 breast, ovarian, colon and pancreatic cell lines. Results: Examination of the pattern of LOH within ovarian tumors with BRCA1, BRCA2, or RAD51C defects compared to tumors without defects in these genes has resulted in the development of a homologous recombination deficiency (HRD) score that has highly significant association with HRD (p=9*10-11). An intermediate class of LOH sizes (&gt;15 Mb but less than a whole chromosome) is highly positive correlated with defective HR, suggesting this class of LOH exists due to double strand DNA break formation and requires repair by HR. The HRD score was validated in two independent ovarian cancer datasets (p=2*10-7 and 9*10-29), and successfully identified breast and pancreatic cell lines with BRCA defects, suggesting it will be effective across multiple tumor types. Conclusions: BRCA1 or BRCA2 mutation carriers have improved outcomes following treatment with DNA damaging agents such as platinum salts, and preclinical studies have demonstrated PARP inhibitor efficacy in BRCA1 or BRCA2 deficient cells. HR deficiency in ovarian cancer is not solely due to germline BRCA1 and BRCA2 mutations, and HR deficiency is not unique to ovarian tumors. Each type of cancer is likely to have a unique spectrum of genetic variants resulting in HRD. The HRD score appears capable of detecting HRD regardless of etiology or mechanism. This score could have clinical utility in breast and ovarian cancer, and could be used to target the use of PARP inhibitors and platinum salts in other 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 3116. doi:1538-7445.AM2012-3116
Abstract 312: Blockade of tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor overcomes tumor regrowth after radiotherapy
Authors: Xu Jingying , Escamilla Jemima , Wu Lily 
Published: August 2012

Abstract
Radiotherapy is one of the major frontline treatments for prostate cancer (PCa). However, a large proportion of patients suffer from tumor recurrence after radiotherapy. Tumor-infiltrating myeloid cells (TIMs), including CD11b+F4/80+ tumor-associated macrophages (TAM) and CD11b+Gr-1+ myeloid-derived suppressive cells (MDSCs), play critical roles in promoting tumoral angiogenesis, tissue remodeling and immunosuppression. Recently several reports suggested that TIMs might play a critical role in mediating tumor regrowth after radiation therapy. Here, we showed that there is enhanced recruitment of both TAMs and MDSCs after 5 days of 3 Gy radiation treatment in subcutaneously implanted RM-1 syngeneic PCa model. Infiltration of two MDSC subsets, CD11b+Gr-1loLy6Chi mononuclear-MDSC (MO-MDSC) and CD11b+Gr-1hiLy6Clo polymorphnuclear-MDSC (PMN-MDSC), are both increased. Although treatment is localized to the tumor site, the effects of radiation are systematic. Dramatic increases of MDSCs and TAMs were also observed in the spleen, lymph nodes and peripheral blood. To better understand the mechanism of enhanced recruitment of myeloid cells to tumors, we performed RT-PCR analysis on tumor tissues for commonly known factors that mediate the recruitment of myeloid cells. Indeed, we found that macrophage colony stimulating factor 1 (M-CSF-1 or CSF-1) increases by 2 fold in irradiated tumors compared to non-irradiated tumors. In vitro migration assays using conditioned medium from irradiated tumor cells increases migration of RAW246.7 macrophages by 4 fold, and this increase is completely blocked by the very selective CSF1R inhibitor, GW2580. Immunohistochemical analysis confirmed the induction of TAMs and MDSC recruitment to tumors, and the effectiveness of GW2580 in blocking their infiltration. Most importantly, combination therapy using GW2580 with radiation synergistically suppressed tumor growth and recurrence. This data highlights the importance of CSF1/CSF1R signaling in the recruitment of TIMs post-radiation treatment and their significant role in promoting tumor re-growth. Moreover, our data could potentially provide a more effective and durable treatment strategy for PCa patients.
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 312. doi:1538-7445.AM2012-312
Abstract 3120: Functional characterization of ERCC1 isoforms in NSCLC
Authors: Friboulet Luc , Thomale Juergen , Olaussen Ken , Ponsonnailles Florence , Dorvault Nicolas , Commo Frederic , Saulnier Patrick , Vagner Stephan , NAKOUZI Nader , André Fabrice , Soria Jean-Charles 
Published: August 2012

Abstract
Background: ERCC1 is a DNA repair protein whose expression is a prognostic and predictive biomarker of chemotherapy effect in NSCLC. Five alternative transcripts of the ERCC1 gene have been described or hypothesized to exist (isoforms 201 to 205). Nevertheless, little is known about the function and relative expression of these isoforms. We explored 3 main questions: a- Which ERCC1 isoforms are detected by clinically validated antibodies? b- Which isoforms are expressed in lung cancer cell lines and patient samples? c- Which isoforms are functional for removal of cisplatin DNA-adducts and potentially relevant as predictors of cisplatin resistance? Methods: To determine the specificity of anti-ERCC1 antibodies, a screening of isoform specific peptide sequences was achieved using a peptide array (Epitope Mapping CelluSpots™). The expression of ERCC1 isoforms was evaluated in 20 lung cancer cell lines and in 123 NSCLC patients by qRT-PCR. We established a functional DNA repair assay by monitoring the accumulation of cisplatin adducts over time with a specific antibody RC-18 (courtesy of Juergen Thomale, Germany). To investigate isoforms functionality, we created stable ERCC1 attenuated A549 cells with Zinc Finger Nucleases technology (Sigma). Using lentiviral constructs we rescued ERCC1 isoforms expression. Results: The 2 monoclonal antibodies, clone 8F1 and 3H11 recognize a conserved region shared by all isoforms of ERCC1 protein, and so, are unable to distinguish the different isoforms. The 5 isoforms were all detected at mRNA level, both in cancer cell lines and in patient tissues. Interestingly, a significant increase in isoform 201 expression was observed in all tumor tissues compared to normal counterparts. We obtained 7 A549 clones harboring a 85-95% decrease in ERCC1 expression. In these cells we observed a 7-fold increase in IC50 of cisplatin accompanied by a significant decrease in the rate of nucleotide excision repair (NER). We are currently exploring isoform function by analyzing DNA repair efficiency in the different stable cell lines. Conclusions: Alternative roles for ERCC1 beyond NER are currently emerging. Our 7 A549 clones, with stable and strong ERCC1 attenuation, provide a very promising tool to analyse all functions of ERCC1. Since most antibodies used to test ERCC1 positivity in patients do not distinguish the different isoforms, it is urgent to characterize their function further, particularly the role of isoform 201 overexpression in NSCLC tumors.
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 3120. doi:1538-7445.AM2012-3120
Abstract 3149: MicroRNA-141 inhibits proliferation and invasion by suppressing the Wnt signaling pathway in renal cell carcinoma
Authors: Yamamura Soichiro , Sharanjot Saini , Shahana Majid , Hirata Hiroshi , Ueno Koji , Chang Inik , Chiyomaru Takeshi , Tanaka Yuichiro , Dahiya Rajvir 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are highly conserved, single stranded, non-coding RNAs of approximately 22 nucleotides that regulate gene expression by posttranscriptional silencing of specific target mRNAs, by repressing translation or cleaving RNA transcripts. miRNAs regulate diverse cellular processes such as cell-cycle progression, proliferation, apoptosis and development. miRNAs have been shown to function as oncogenes or tumor suppressor genes. MicroRNA-141 has recently been reported to play a role in the epithelial to mesenchymal transition (EMT) process and the expression of miR-141 is inversely correlated with tumorigenicity and invasiveness in several human cancers. The function of miR-141 in renal cell carcinoma has not been studied, therefore we studied the functional effects of miR-141 on renal cell carcinoma. We found that miR-141 was down regulated in human kidney cancer tissues compared with adjacent normal tissues. We also found that miR-141 was down regulated in renal cell carcinoma human cell lines, 769P, 786-O and ACHN compared with normal kidney cell line, HK-2. Transfection of miR-141 into renal cell carcinoma cells promoted apoptosis, inhibited in vitro cell proliferation and inhibited cell invasion. We found that miR-141 has a binding site in 3′UTR of the TCF7L2 (Transcription factor 7-like 2) gene which can activate the canonical Wnt pathway. miR-141 was found to down regulate expression of TCF7L2 by targeting its 3′ UTR as shown by luciferase reporter assays in renal cell carcinoma. Luciferase assays using T cell factor (TCF) reporter plasmids also showed that miR-141 represses TCF/LEF transcriptional activity, indicating that miR-141 suppresses the canonical Wnt pathway in renal cell carcinoma. Our results demonstrate that miR-141 suppresses malignancy by targeting TCF7L2 and inhibiting the Wnt signaling pathway in renal cell carcinoma. Source of Funding: Grants R01CA138642, VA Research Enhancement Award Program (REAP), and VA Merit Review grants
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 3149. doi:1538-7445.AM2012-3149
Abstract 3150: miR-100 in ovarian cancer cell lines
Authors: Howell Viive M. , Dickson Kristie-Ann , Kan Casina W. S. , Hahn Michael A. , Marsh Deborah J. 
Published: August 2012

Abstract
MicroRNA (miRNA), small non-coding RNA sequences that regulate gene expression, have the potential to function as tumor suppressors or oncogenes. To determine the contribution of miRNA to ovarian oncogenesis this project sought to identify dysregulated miRNA and their targets in ovarian cancer cell lines. miRNA expression profiling was performed on 6 serous epithelial ovarian cancer (SEOC) cell lines and normal ovarian surface epithelial (OSE) cells. miRNAs differentially expressed between SEOC and OSEs were selected for further analyses and candidate target genes identified by prediction algorithms. miRNA expression was restored by transient transfection of miRNA mimics or stable transduction of lentiviral vectors expressing miRNA precursors. The effects on the expression of 2 predicted targets, SMARCA5 and FRAP1, were investigated using a luciferase reporter system, quantitative RT-PCR (qPCR) and immunoblotting. The effect of miRs on cellular proliferation was also explored. Expression profiling identified miR-100 as having &gt;5-fold lower expression in SEOC vs OSE cells. Seed sequences or binding sites for miR-100 were identified in the 3′UTRs of SMARCA5 and FRAP1. Using a luciferase expression system in OVCAR-3 cells, a miR-100 mimic repressed expression of SMARCA5 3′UTR by 40 % (p&lt;0.0001), and FRAP1 3′UTR by 30% (p&lt;0.0005). No effect of the mimic was observed when the predicted miR-100 binding sites in each gene's 3′UTR were mutated. Stable transduction of OV202 cells with pre-miR-100 resulted in a 3-5 fold increase in miR-100 expression. This stably transduced SEOC cell line showed decreased cellular proliferation, and repressed transcript and protein levels of SMARCA5/SNF2H and FRAP1/mTOR compared with the cell line transduced with the empty lentiviral vector. We identified miR-100 as a modulator of cellular proliferation in OV202 cells, possibly through regulation of SNF2H, a chromatin remodelling factor, and mTOR a phosphatidylinositol kinase-related kinase. miR-100 is located in an area of frequent chromosomal loss in aggressive SEOC suggesting a mechanism for reduced expression in these cells. Future work will investigate the potential of miR-100 as a novel therapeutic target for the treatment of 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 3150. doi:1538-7445.AM2012-3150
Abstract 3159: Differential miRNA expression profiling of rectal and colon cancers using deep sequencing
Authors: Chen Zhenbin , Mu Bing , Qin Hanjun , Wang Jinhui , Wu Xiwei , Gao Harry , li Wenyan , Garcia-Aguilar Julio 
Published: August 2012

Abstract
Background: miRNAs are small regulatory elements involved in regulating gene expression. They have been shown to play a role in tumor initiation, progression, and metastasis in many cancers and their expression is often tissue-specific. Cancers of the large bowel are often grouped together as colorectal cancers; but tumors from different locations require different treatment and have different prognosis and molecular characteristics. We tested the hypothesis that cancers of the colon and rectum have different molecular miRNA profiles that can be used to distinguish between these cancer types. Methods: We collected 40 pretreatment rectal cancer biopsies and 20 pretreatment surgical colon cancer specimens. All samples were formalin fixed and paraffin embedded (FFPE). Tumor cells were microdissected manually under inverted microscopy and total RNA was extracted. A miRNA expression profile for rectal and colon cancer was generated using deep sequencing, and miRNA expression in each cancer type was compared using T-test and multiple testing (Q-bound &lt;0.05) to determine significant miRNA expression changes in rectal versus colon cancer. Results: 143 miRNAs were differentially expressed between rectal and colon cancer tissues (Q-bound &lt;0.05); 106 miRNAs were up-regulated and 37 were down-regulated in rectal cancer compared to colon cancer. Thirteen miRNAs showed a greater than 2-fold increase in expression in rectal cancer compared to colon cancer (mir-1291, mir-1248, mir1973, mir-3653, mir-483-5p, mir-720, mir-3647-3p, mir3687, mir-3607-3p, mir4286, mir-1274b, mir-483-3p, and mir3648). Six miRNAs showed a greater than 1.5-fold decrease in rectal cancer compared to colon cancer (mir-374a, mir-3613-5p, mir-362-3p, mir-340, mir-3, and mir-424). Based on these significant expression differences, the unique miRNA expression profiles of rectal and colon cancer were used to separate these cancers by hierarchical cluster analysis (p&lt;0.0001). Conclusions: We identified a number miRNAs that are differentially expressed between rectal and colon cancer. These tissue-specific miRNA expression profiles may help us understand the biological differences between colon and rectal cancer, which may lead to improved treatments.
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 3159. doi:1538-7445.AM2012-3159
Abstract 3209: Metformin suppresses the growth and modulates the metabolic profiles of pancreatic cancer cells under hypoxia in an IKKα-dependent manner
Authors: Emami-Shahri Nia , Maniati Eleni , Bossard Maud , Hagemann Thorsten 
Published: August 2012

Abstract
Nuclear factor-βB; (NF-κB) controls a range of genes involved in inflammation, cell survival, growth and apoptosis. The dysregulated NF-κB pathway has been found to be involved in carcinogenesis and cancer progression. An IKKα-deleted mouse pancreatic cancer cell line was generated using a lentiviral construct with an shRNA. We investigated the effects of metformin, an anti-diabetic drug, on the cell proliferation and metabolism of these cells, under normoxic and hypoxic conditions. A high dose (5 mM) of metformin under normoxic conditions suppressed the growth of both wild-type and IKKα knockdown cell types; however, under hypoxic conditions IKKα knockdown cells were more sensitive to treatment than their wild-type counterpart (p &lt; 0.001). Metabolic assays revealed that metformin treatment under normoxic conditions decreased the oxidative phosphorylation (OXPHOS) whilst increasing the lactate production of both cell types to similar levels. Under hypoxia, metformin treatment of both cancer cells resulted in decreased OXPHOS, with a more profound effect on the IKKα knockdown cells, and a significant decrease in lactate production in the IKKα knockdown cells only (p &lt; 0.001). We believe our findings have implications for understanding the molecular mechanisms of metformin as a therapeutic agent in cancer treatment.
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 3209. doi:1538-7445.AM2012-3209