bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B66: PI3 kinase inhibitor enhances the efficacy of BO-1509 by suppressing MRN complex in lung cancer xenografted mice.
Authors: Sanjiv Kumar 
Published: June 2012

Abstract
Lung cancer is the most common cause of cancer-related death in men and women. Incidence rate of lung cancer is keep increasing year after year. Lot of progress has been made in field of lung cancer therapy to prolong lifespan of patients, but it is still inadequate. In our previous study, novel alkylating agent BO-1012 in combination with arsenic trioxide shown to have very good therapeutic efficacy in lung cancer H460 Xenografted mice. Meanwhile, we also observed activation of survival and DNA repair protein molecules in cells treated with BO-1012. In further development of drug up on modification in functional group of BO-1012, we observed enhanced lethal effect of BO-1509 in lung cancer cells. To overcome activation of survival and DNA repair protein we combined BO-1509 with PI3 kinase inhibitor LY294002. Synergism being found between two drugs in several lung cancer cells like H460, CL-1-5, CL-25 and CL-83 in culture. Furtherome, alone at doses of 5 mg/kg and 10 mg/kg BO-1509 by iv for five times reduce tumor burden 50% and 70% in H460 and CL-1-5 xenografted mice respectively. But when it combined with PI3 kinase inhibitor (LY294002) 40 mg/kg injected by ip for 10 times, tumor burden reduced 85% in H460 and 86% in CL-1-5 xenografted mice. Initial finding suggests that synergism between BO-1509 and PI3 kinase inhibitor may be due to inhibitory effect of PI3 kinase on Mre11 and Nbs1 proteins of MRN complex which play important role in homologous repair pathway. Mre11 and Nbs1 protein were found to be elevated upon treated with of BO-1509 in H460 cells. PI3 kinase inhibitor also prevents BO-1509 activated nuclear localization of Rad51 in H460 and CL-1-5 cells which is confirmed by using confocal microscopy. Based on H2AX foci formation assay, half of double strand break (DSB) in cell induced by BO-1509 get repaired by 72 h, while cells treated in combination of BO-1509 with PI3 kinase inhibitor still maintain DSB damage, which may enhance the lethal effect of BO-1509 to H460 and CL-15 cell. Complete blood profile, biochemical enzyme analysis and histopathology of major organ suggest no significant toxicity in mice treated with BO-1509 alone or in combination with PI3 kinase inhibitor.
In conclusion the combination with PI3 inhibitor increases the efficacy of BO-1509 by suppressing the DNA repair and survival factor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B66.
Abstract B77: KRAS mutational status impact progression-free survival of patients treated with platinum-based chemotherapy in NSCLC.
Authors: Marabese Mirko , Rulli Eliana , Bettini Anna , Garassino Marina C. , Longo Flavia , Moscetti Luca , Pavese Ida , Lauricella Calogero , Broggini Massimo , Farina Gabriella 
Published: June 2012

Abstract
Background: KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatment. However, such evidence is only drawn from retrospective series giving controversial results. Moreover, it is possible that the various KRAS mutations differently affects prognosis, carcinogenesis and drug response as demonstrated in preclinical setting. Aim of this study is to prospectively assess the prognostic value of KRAS mutations in NSCLC patients treated with a first line platinum containing regimen. This is a properly planned ancillary study within the TAILOR trial (NCT00637910) which is mainly focused on the second line.
Methods: Tissue and blood samples were collected at diagnosis in the whole cohort of registered patients. KRAS status was centrally determined with standard direct sequencing and KRAS genotype was assessed by real time PCR. The primary hypothesis is a difference in PFS according to KRAS mutational status; the impact of the three more frequent KRAS substitutions (G12C, G12V, and G12D) was also explored. The analysis was planned at occurrence of 200 events (HR≥1.49, power 80%, 2-tailed alpha 10%), in a Cox model adjusting for Performance Status and radical surgery.
Results: Out of 565 patients registered, 341 (60.5%) were evaluable for KRAS and 85(25%) were mutated.
At a median follow-up of 17 months KRAS mutated patients showed a statistically significant worse PFS (HR 1.42 95%CI 1.06–1.94; p=0.02). No differences among doublets were observed in KRAS mutated patients. The most frequent KRAS mutations were: G12C (36.4%), G12V (21.1%), G12D (16.4%), others (25.9%). Prognostic differences among variants are observed. Final genotype analyses are ongoing.
Conclusions: This is the first prospective, pre-planned and adequately sized evaluation of KRAS in NSCLC. Patients mutated for KRAS seem to have a higher risk of progressing. These results suggest that KRAS mutation epidemiology in this setting highly differs from that of colon cancer. Clinical data suggest that tailored strategies for these patients are warranted and our preclinical studies will help in clarifying the molecular mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B77.
Abstract B82: High frequency of hypermethylation at the 14-3-3 sigma to gene silencing in breast cancer.
Authors: Joaquina Martinez-Galan , Ramon Delgado J. , Blanca Torres-Torres , Arancha Gonzalez-Vicente , Jesus Soberino , Cynthia Gonzalez-Rivas , Julia Vozmediano 
Published: June 2012

Abstract
Background: Expression of 14-3-3 sigma is induced in response to DNA damage, and causes cells to arrest in G(2). Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. Objetive: To study the relation of 14-3-3 sigma gene promoter hypermethylation and its transcription expression levels in sporadic breast carcinogenesis.
Material and Methods:This is a prospective study we quantified methylation levels of promoter 14-3-3 gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer.
Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%, N1;30%, N2;7%), tumor size (T1;58%, T2;35%, T3;4%, T4;4%) and grade G1; 20%, G2;37%, G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047). The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p&lt;0.05), nodal positive status (p&lt;0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p&gt;0.05). Conclusions: The recent identification of novel 14-3-3sigma-associated proteins by a targeted proteomics approach implies that 14-3-3sigma regulates diverse cellular processes, which may become deregulated after silencing of 14-3-3sigma expression in cancer cells. Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B82.
Abstract B84: HCI-2528 is a potent inhibitor of LSD1 with improved druglike characteristics.
Authors: Stephens Bret J. , Sorna Venkataswamy , Theisen Emily , Vankayalapati Hariprasad , Warner Steven , Bearss David , Sharma Sunil 
Published: June 2012

Abstract
Lysine Specific Demethylase 1 (LSD1/KDM1A) plays an important role in the regulation of histone methylation at lysine residues, and is currently being validated as an attractive therapeutic target for many diseases, particularly for multiple forms of cancer. Methylation of lysine residues on histones can signal transcriptional activation or repression depending on the specific residue involved. H3K4me2 is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by LSD1 is thought to prevent expression of tumor suppressor genes important in human cancer. In contrast, methylation of H3K9 is a repressive mark and LSD1 activity has been shown to upregulate tumor promoting pathways. Thus, LSD1 is emerging as an important target for the development of specific inhibitors as a new class of antitumor drugs. Several LSD1 inhibitors have been reported, but they have shown poor selectivity and/or pharmacological properties, making further exploration of LSD1 biology difficult. We previously reported the identification of CIT-0665, an LSD1 inhibitor identified through a virtual screening effort in our lab. Evaluation of the structure activity relationships of multiple analogs of our LSD1 inhibitor led to the identification of HCI-2528, which is more potent and exhibits improved drug like properties. Using a cell viability assay, a large panel of cancer cell lines was tested for sensitivity to HCI-2528. In addition to the well-documented sensitivity of breast cancer cell lines, we also found that Ewing's sarcoma cell lines are uniquely sensitive to LSD-1 inhibition. We are currently engaged in a bioinformatic effort to determine possible mechanisms of sensitivity from our studies, and performing xenograft studies in mice. In conclusion, HCI-2528 is a novel LSD1 inhibitor with activity in biochemical and cell-based assays.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B84.
Abstract B97: Microarray analysis in ependymomas, astrocytomas, and medulloblastomas: Identification of potentially related metabolic pathways.
Authors: Perez-Gonzalez Oscar , Cardenas-Cardos Rocio , Rivera-Luna Roberto , Macias-Vega Miguel 
Published: June 2012

Abstract
Purpose: Primary Central Nervous System Tumors (PCNST) are the most frequent solid neoplasias in childhood, in particular those derived from astrocytes, aracnoids and ependimum. The prognostic criteria is based on the anatomic localization, tumor size and surgical accesibility for resection. Nevertheless, this criteria is not enough to predict a therapeutic success in all patientes, either knows with exactitude the implied underlying biological process in paediatric cerebral tumors. The goals of this research are to identify gene expression profiles and integrate metabolic pathways potentialy related to each histological subtype.
Methods: We included neoplastic tissue samples from pediatric patients with ependymomas, astrocytomas y medulloblastomas treated at the National Institute of Pediatics, Mexico. Diagnostic approach and treatment protocols were those stablished by the Pediatric Oncology Service considering only those patients with a signed consent. We purified total RNA from these samples using RNAeasy mini kit (Qiagen), considering those samples with 8 or more RIN (RNA Integrity Number) useful for microarray hybridization on the GeneChip® Human Gene 1.0 ST Array (Affymetrix). Statistic analysis was performed with Affymetrix Expression Console and Partek's Genomics Suite. We also used the Database for Annotation, Visualition and Intgrated Discovery (DAVID, Bioinformatics Resources v6.7) for data minning in order to identify metabolic pathways potentialy related to each histological subtype with the differential gene expression results.
Results: We considered all microarrays that showed good correlation (index 0.8 to 1.0) for the statistical analysis. We found a list of genes differentially expressed according to the hystologic subtype (ependymomas, astrocytomas and medulloblastomas), and then we integrated the metabolic pathways apparently related to differentially expressed genes with DAVID. Details of these results will be presented at the meeting.
Conclusion: These results show that gene expression profiles may clearly differentiate ependymomas, astrocytomas and medulloblastomas according to their histological subtype. Differential gene expression profiles in these PCNST are being analyzed as a diagnostic tool in order to provide a more accurate allocation criteria for antineoplastic treatments based not only on their own genomic profiles but in the neoplastic behavior potentially related to the metabolic pathways results.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B97.
Abstract C134: Herceptin-targeted siRNA nanoparticles inhibit the growth Her2-positive breast cancer tumors in vivo.
Authors: Zuckerman Jonathan E. , Han Han , Medrano Leonard , Choi Chung Hang J. , Davis Mark E. 
Published: June 2012

Abstract
We have recently demonstrated the feasibility of using targeted, polymer-based siRNA nanoparticles in the clinic1. This delivery system involved the use of the human protein transferrin (Tf) that is displayed on the surface of the nanoparticles to engage cancer cell surface, transferrin receptors (TfR). Here, we demonstrate the modular nature of this siRNA delivery system by tailoring both the targeting agent and siRNA component of the nanoparticle to Her2 positive breast cancers. Specifically, we show that the siRNA nanoparticle delivery system can be modified to include an antibody targeting agent (Herceptin) without any significant alteration to size, charge, and pharmacokinetic behavior. We also show that in vivo treatment of Her2 positive breast cancer tumor xenografts with Herceptin-targeted nanoparticles containing siRNA against Her2 results in a more robust anti-tumor response than either Herceptin alone or Herceptin-targeted nanoparticles containing control siRNA. These data demonstrate how nanoparticles containing the combination of antibodies and siRNA can be used to achieve enhanced therapeutic treatment against clinically validated cancer targets.
References:
1. Davis, M.E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C134.
Abstract C151: Maspin is regulated by the alternative NF-κB subunit in androgen-insensitive prostate cancer cell lines.
Authors: Guo Feng 
Published: June 2012

Abstract
Dysregulation of Maspin expression and constitutive activation of NF-κB subunits are important events in tumorigenesis of prostate cancer. Recent finding points that RelB, which contributes to the alternative NF-κB activity, interferes with carcinogenesis in the prostate. We report here, that both the classical (predominantly p50/RelA heterodimers) and the alternative NF-κB activities (p52/RelB heterodimers) are constitutively present in androgen-insensitive human prostate cancer cells. An inverse relationship of Maspin and RelB expression is observed in prostate cancer tissues at the later stage. TNF-α signaling triggers the nuclear accumulation of RelB and the concomitant reduction of Maspin expression in a time-dependent manner. In addition, the proteasome inhibitor-induced Maspin expression is accompanied by the reduction of RelB expression. A successful depletion of RelB expression, but not RelA expression, induces Maspin expression. RelB-deficiency abrogates the proteasome inhibitor-induced Maspin expression. Moreover, we demonstrate that the enforced expression of RelB protein in prostate cancer cells inhibits Maspin expression. We propose that RelB is an essential molecule controlling the endogenous and the proteasome inhibitor-induced Maspin expression. Developing a RelB-targeted therapeutic intervention, which might be coupled with the induction of a tumor suppressor Maspin, is valuable in treating advanced, metastatic prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C151.
Abstract C165: Breast cancer, statins, and 3-D cell culture.
Authors: Mullen Peter J. , Goard Carolyn A. , Wasylishen Amanda R. , Pandyra Aleksandra , Penn Linda Z. 
Published: June 2012

Abstract
Statins are widely used to lower serum cholesterol levels. They act by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR), the rate-limiting step in the mevalonate pathway. Recent work also shows that statins could be used as anticancer therapeutics, particularly in breast cancer. This study presents a preliminary rationale for the use of statins as a therapy in breast cancer.
We characterized a panel of breast cancer cell lines for sensitivity to fluvastatin, using proliferation and cell-death assays. We also screened for differences in activity of the electron transport chain and glycolysis after fluvastatin treatment. We then began to expand on these results using 3D cell culture techniques to offer a more representative tumor model.
The panel of breast cancer cell lines showed a range of sensitivity to fluvastatin, with MTT50 for 72 h treatment varying from 0.7 μM for MDA-MB231 cells to 162.8 μM in BT474 cells. Interestingly, triple negative cell lines were in the sensitive range. Differences in cell cycle populations were also observed, with a representative panel of sensitive cells showing an increased G1/G0 arrest and decrease in S-phase population when compared to insensitive cell lines. Delving deeper, mitochondrial respiration was decreased in the sensitive cell lines. We also observed greater changes in morphology in the sensitive cell lines than the insensitive when grown in 3D cell culture, potentially offering more relevance to our observations.
These results confirm that there is a range of sensitivities to fluvastatin in breast cancer cell lines, allowing for further studies to determine the cause of these differences. The hints at metabolic differences could also lead to novel co-treatments with statins and greater therapeutic benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C165.
Abstract C172: A synthetic glycolipid induces macrophage-mediated apoptosis of cancer cells via nitric oxide-dependent downregulation of thoc1 gene.
Authors: Lin Yong-Shiang , Lin Chao-Hsiung , Lin Chun-Cheng , Fu Shu-Ling 
Published: June 2012

Abstract
Activation of Toll-like receptor 4 (TLR4) triggers both innate and adaptive immunity. We previously developed a synthetic TLR4 agonist, CCL-34, which can induce anticancer immunity in vitro and in vivo. The CCL-34-activated macrophages were shown to induce nitric oxide (NO)-dependent apoptosis of cancer cells. In addition, the THO complex 1 (thoc1) gene was suppressed in cancer cells co-cultured with CCL-34-activated macrophages and in tumors of CCL-34-treated mice, suggesting the involvement of Thoc1 in the CCL-34-induced anticancer activity. It has been shown that Thoc1 promoted cell survival and was overexpressed in many cancer cells. However, regulation of thoc1 and its downstream effectors in Thoc1-mediated cell survival remains unknown. In this study, we investigated the role of Thoc1 in the cancer cell apoptosis induced by CCL-34-activated macrophages and the underlying molecular mechanisms. Our data showed that the suppressed Thoc1 in bladder cancer cells (MBT-2) co-cultured with CCL-34-activated macrophages was restored by iNOS inhibitor (L-NMMA), and direct treatment of MBT-2 cells with NO donor repressed Thoc1 expression. Moreover, treatment of either CCL-34 or NO donor resulted in the suppression of thoc1 promoter activity in MBT-2 cells, whereas mutations in certain region of this promoter region abolished such repression. Notably, MBT-2 cells overexpressing thoc1 (MBT/thoc1) exhibit higher resistance to the cytotoxicity induced by treatment of NO donor or CCL-34-activated macrophages than MBT-2 cells, while both treatments suppressed Bcl-2 expression in MBT-2 cells but not in MBT-2/thoc1 cells. Together, our results demonstrate that NO-mediated thoc1 downregulation is a key step in the cancer cell apoptosis induced by CCL-34- treated macrophages. In addition, the decreased expression of thoc1 could lead to downregulation of Bcl-2 and subsequent induction of cancer cell apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C172.