bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5615: Global DNA methylation by LUMA predicts breast cancer risk in a population-based study
Authors: Xu Xinran , Gammon Marilie D. , Wetmur James G. , Teiltelbaum Susan L. , Bradshaw Patrick T. , Neugut Alfred I. , Santella Regina M. , Chen Jia 
Published: June 2012

Abstract
Global methylation dysregulation is a hallmark of cancer cells. Global methylation measurement in peripheral blood may be a predictor of cancer risk and prognosis. In this study, we used two independent assays, LUminometric Methylation Assay (LUMA) and LINE-1 methylation by pyrosequencing, to assess the global methylation content in the peripheral blood DNA from the Long Island Breast Cancer Study Project, a population-based case-control study. We examined the association between global methylation levels and: 1) the risk of developing breast cancer among 1055 cases and 1101 controls using logistic regression models; 2) the risk of mortality among breast cancer cases using Cox proportional hazards models; and 3) one-carbon metabolism genetic polymorphisms and dietary intake among controls using ANOVA. LUMA methylation levels were higher among cases (mean: 57.3%) than among controls (mean: 52.4%; p&lt;0.001). Compared to women in the lowest quintile of LUMA methylation, those in the highest quintile had a 2.41-fold increase in the risk of developing breast cancer (95% CI: 1.83-3.16; p for trend &lt; 0.0001). Risk was strongest for in situ breast cancer (OR: 6.18; 95% CI: 3.34-11.43), although the estimate is based on small numbers; but the association did not vary by other tumor characteristics, life-style or several established breast cancer risk factors. Among cases, there was an indication that high LUMA levels were associated with reduced breast cancer-specific mortality. Among controls, LUMA levels were associated with two SNPs in the one-carbon metabolism pathway, MTHFR C677T (p=0.001) and MTRR A66G (p=0.018), but not with dietary intake of one-carbon related nutrients. No association was observed between LINE-1 methylation and breast cancer risk, breast cancer-specific mortality, one-carbon metabolism SNPs or nutrients, or LUMA methylation. Our results suggest that LUMA methylation levels in peripheral blood DNA are associated with breast cancer development and progression.
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 5615. doi:10.1158/1538-7445.AM2011-5615
Abstract 587: B-Raf status predicts response to pharmacological activation of p53 in melanoma
Authors: Lee John T. , Brafford Patricia A. , Halloran Molly B. , Schultz David C. , Herlyn Meenhard 
Published: June 2012

Abstract
The formulation of highly-potent and specific inhibitors of the MAPK pathway has yielded several promising candidates and these are currently under advanced clinical development; however, early data suggests that inhibition of the MAPK pathway will not be sufficient to elicit sustained tumor regression in malignant melanoma. Thus, other pathways likely need to be therapeutically exploited to achieve sustained responses in melanoma patients. Because the tumor suppressor protein p53 is functional, yet inactive, in nearly 100% of melanomas, we sought to identify novel pharmacological activators of p53 in melanoma. To accomplish this goal, we employed a high-throughput screening strategy that identified hycanthone, a compound previously characterized for anti-schistosomal activity, as a specific activator of p53 function. In vitro characterization of hycanthone demonstrated that it activates the p53-transcriptional response leading to cell cycle arrest and subsequent apoptosis in a panel of melanoma cell lines harboring wild-type p53; these effects are largely absent in isogenic cells expressing p53 shRNA or alternative lines expressing mutant p53. Screening of a substantial panel of cell lines revealed that activation of p53 initiated anti-melanoma effects exclusively in cells that expressed mutant Braf, indicating that activated MAPK signaling may serve as a correlate to predict response to pharmacological activators of p53 in melanoma. However, additional experimentation has demonstrated that, instead, it is the presence of mutations in Braf, rather than the resultant MAPK activity, that predicts response to p53 activation. Studies investigating the mechanistic details governing this biological phenomenon are ongoing. Collectively, our data indicate that reactivation of p53 in melanoma, like multiple other tumors, can elicit an anti-tumor phenotype; however, this response is negatively modulated by the expression of mutant Braf, which would suggest that patients should be prospectively genotyped to identify potential responders to p53 reactivators.
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 587. doi:10.1158/1538-7445.AM2011-587
Abstract 594: MDM2 inhibition by MI-219 elicits differential molecular effects in wild-type p53 lymphoma cells
Authors: Sosin Angela M. , Yang Dajun , Mohammad Ramzi M. , Al-Katib Ayad 
Published: June 2012

Abstract
Mutations in TP53 occur in 50% of all cancers but are far less common in hematological malignancies. The activity of wild-type p53 (wt-p53) is frequently compromised in lymphomas by overexpression of MDM2. Small-molecule inhibitors (SMIs) that can disrupt the MDM2-p53 interaction and restore p53 function may be an attractive therapeutic strategy. Although response to MDM2 inhibition has previously been determined to greatly depend on p53 status, p53 functional consequences are not fully understood in the presence of MDM2 SMIs. We recently demonstrated striking growth inhibition of two different classes of MDM2 SMIs: Nutlin-3; a cis-imadiazole and MI-219; a spiro-oxindole. Growth inhibition was seen in wt-, but not mutant-, p53 lymphoma cells and did not affect MDM2 E3 ligase activity.
In this study, we report that MDM2 inhibition exerts differential molecular effects in wt-p53 lymphoma cells. We found that wt-p53 cell lines, FSCCL and KM-H2, are sensitive to MDM2 inhibition in a time- and dose-dependent manner. Moreover, MI-219 showed greater potency compared to analogous concentrations of Nutlin-3. MI-219 caused more pronounced cell cycle arrest of both cell lines in G0/G1 over a 72 hour time period. Treatment stabilized and activated p53 as well as upregulated p21 and MDM2 protein levels. MG132 and cycloheximide treatments were performed in the presence or absence of MI-219 to determine whether the increase in p53 was due to dissociation from MDM2 and not increased degradation or stabilization. Co-immunoprecipitation confirmed MDM2 SMI disruption of the MDM2-p53 interaction. There was clear evidence of apoptosis in FSCCL, but surprisingly not in KM-H2, as indicated by TUNEL/PI staining (54.39% ± 4.78 vs. 1.32% ± 0.52 after 24 hours). Additionally, apoptosis markers were induced at both mRNA (p53AIP1) and protein levels (caspase-3 and PARP cleavage) after exposure to MI-219 in FSCCL compared to KM-H2. The molecular mechanisms by which MDM2 SMIs exert this differential effect are currently under investigation.
Our data presents the preclinical structure for further exploration of MI-219 as a therapeutic approach in the treatment of wt-p53 lymphomas. However, based on our findings, we conclude that additional insights to p53 biology are necessary to maximize their therapeutic potential from preclinical to clinical development.
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 594. doi:10.1158/1538-7445.AM2011-594
Abstract 609: Frondoside antagonizes the prostaglandin E receptor EP4 and inhibits breast tumor metastasis
Authors: Ma Xinrong , Kundu Namita , Collin Peter , Fulton Amy M. 
Published: June 2012

Abstract
Sea cucumber has been used as a folk medicine for many conditions and recently antitumor activities have been described. Frondoside A, a triterpenoid glycoside isolated from the sea cucumber Cucumaria frondosa, as well as the related compound Frondanol A5 inhibit growth of pancreatic, colon and breast tumor cell lines in vitro and show activity in a primary prevention model of colon cancer. The cyclooxygenase 2 pathway contributes to growth and progression of many solid tumors by multiple mechanisms. The COX-2 product, prostaglandin E2 (PGE2) contributes to malignancy by acting on a family of four G-protein-coupled receptors (EP1, EP2, EP3, EP4). We have shown that both human and murine breast tumor cell lines express all EP receptors and that EP4 contributes to metastatic potential in a syngeneic murine model of metastatic breast cancer. Other laboratories have also provided evidence that EP4 promotes malignancy but a paucity of effective EP4 antagonists has slowed the development of clinically evaluable EP-targeted compounds. Based on the reported anti-inflammatory properties of Frondoside A, we asked if this compound has EP antagonist properties. We now report the novel finding that Frondoside A is a potent antagonist of EP4 and, to a lesser degree, antagonizes EP2. Frondoside A inhibits the binding of radio-labeled PGE2 to Chem-1 cells expressing EP4 or HEK cells transduced to express EP2. Using EP4-expressing MDA-MD-231 human breast cancer or murine mammary tumor cell line 66.1, we show that EP4-mediated activation of adenylate cyclase is also blocked by Frondoside A indicating both pharmacologic and functional EP4 receptor antagonism. We determined the effect of Frondoside A on metastatic potential of line 66.1 tumor cells. Treatment of 66.1 cells with non-cytotoxic concentrations of Frondoside A prior to i.v. administration of tumor cells into syngeneic Balb/cByJ female mice reduced lung colonizing capacity by 58%. These studies describe a potent metastasis inhibitory activity of Frondoside A and show, for the first time, that this compound may be a potent novel EP4/EP2 antagonist with activity in a model of metastatic breast cancer.
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 609. doi:10.1158/1538-7445.AM2011-609
Abstract 61: Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with clinical outcome of lung adenocarcinoma
Authors: Shinjo Keiko , Kondo Yutaka , Okamoto Yasuyuki , Yokoyama Toshihiko , Usami Noriyasu , Fujii Makiko , Murakami Hideki , Osada Hirotaka , Sekido Yoshitaka 
Published: June 2012

Abstract
Background: Lung cancer is the leading cause of cancer-related death worldwide. While targeted therapy, such as tyrosine kinase inhibitors (TKIs), has been used against the non small cell lung cancers (NSCLCs) patients with epidermal growth factor receptor (EGFR) mutation, not all the patients received benefit from TKIs. Epigenetic alterations have been recognized as one of the important mechanism of NSCLCs. The aim of this study is to clarify the significance of DNA methylation, especially the clinical impacts of CpG island methylator phenotype (CIMP), in NSCLCs. Methods: Using methylated CpG island amplification-microarray (MCAM), a genome-wide DNA methylation analysis, 41 lung adenocarcinomas (AdCas) were analyzed. DNA methylation of newly identified genes from MCAM analysis was further examined in another cohort of 86 AdCas with bisulfate pyrosequencing method. Results: Unsupervised hierarchical cluster analysis revealed that DNA methylation was extensively accumulated in one subgroup (n=4, 9.8%), which may represent CIMP tumors (651 genes vs. 354 genes, P=0.0004). DNA methylation status of newly identified 7 CIMP markers revealed that 8 (9.3%), 12 (14%), and 66 (76.7%) were classified into CIMP-high, CIMP-low, and CIMP-negative tumors, respectively. CIMP-high tumors showed no EGFR mutations and frequent exposure to smoking. In addition, these tumors had worse prognosis than the other tumors (P=0.035), suggesting that CIMP-high tumors have characteristic clinical features, which may represent an alternative mechanism to the EGFR mutation. Treatments of NSCLC cell lines showed that CIMP positive AdCa cell lines are sensitive to DNA demethylating agent regardless of EGFR status. Conclusions: Our data suggest that CIMP in AdCas appears to be a unique subgroup, which has distinguished clinical traits from the other AdCas. Applying DNA demethylating agent to CIMP-high tumors might be a new strategy for the treatment of NSCLCs without EGFR mutation.
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 61. doi:10.1158/1538-7445.AM2011-61
Abstract 620: Development of a dual protein farnesyltransferase -geranylgeranyltransferase-I inhibitor with antitumor activity against human cancer cells
Authors: Kazi Aslamuzzaman , Luo Yunting , Berndt Norbert , Fletcher Steven , Cummings Christopher , Lawrence Harshani , Hamilton Andrew D. , Sebti Said M. 
Published: June 2012

Abstract
Many low molecular weight GTPases such as Ras, Ral and Rho require posttranslational farnestylation or geranylgeranylation for mediating malignant transformation. This prompted the development of farnesyltransferase (FT) inhibitors (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) as potential anticancer agents. However, when cancer cells are treated with FTIs, K-Ras becomes geranylgeranylated suggesting that inhibition of both FT and GGT-1 may be required to inhibit tumors harboring K-Ras mutations. Recently our group has developed a series of dual FT and GGT-1 inhibitors based on an ethylenediamine scaffold. Among these dual inhibitors FGTI-2734 was most potent in vitro (FT IC50 = 250±190 nM and GGT-1 IC50 = 520±90 nM). In human cancer cells FGTI-2734 inhibits potently HDJ-2 farnesylation, Rap 1A geranylgeranylation and K-Ras prenylation. Furthermore, FGTI-2734 inhibits the phosphorylation of Erk1/2, Akt and S6K, induces p27 accumulation and inhibits potently tumor cell growth. Finally, FGTI-2734 significantly reduces survivin protein levels, and reduction of survivin levels is associated with induction of apoptosis. Thus, this single molecule with dual FT and GGT-1 inhibitory activities may have distinct advantage over selective FTIs and GGTIs and warrants further advanced pre-clinical studies.
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 620. doi:10.1158/1538-7445.AM2011-620
Abstract 626: Specific targeting of cancer cells with RNA aptamers
Authors: Cerchia Laura , Esposito Carla Lucia , Catuogno Silvia , Iaboni Margherita , Draetta Giulio , Condorelli Gerolama , de Franciscis Vittorio 
Published: June 2012

Abstract
A great promise in developing specific molecular probes for disease biomarker discovery and for diagnostic and therapeutic applications is recently represented by the intact cell-based SELEX (Systematic Evolution of Ligands by EXponential enrichment) strategy that allow to select nucleic acid aptamers against living cells. Indeed, using cell-SELEX to target proteins expressed on the cell surface permits to develop aptamers that are able to discriminate between even closely related target cells. This strategy has the advantage of a direct selection of ligands without prior knowledge of the target molecules and enables the identification of aptamers that bind large cell surface-specific markers, in their native conformation.
Recently, by coupling a differential whole-cell SELEX protocol to human glioma and NSCLC cell lines we addressed the possibility to isolate aptamer molecules that may target cancer specific cell surface bound proteins.
We isolated a set of 2’fluoro-pyrimidines modified RNA aptamers that are specific for different targets that are highly expressed on the tumor cell type used and underepresented on other cancer cell types tested.
Remarkably, two of these aptamers bind at high affinity and high specificity to the extracellular domain of two human receptor tyrosine kinases (RTKs), EGFR and Axl respectively. Following binding, both aptamers hamper ligand-dependent receptor dimerization and autophosphorylation. Further, depending on the targeted RTK, the selected aptamers cause inhibition of cell proliferation and selective cell death in vitro and in vivo.
Since an obvious advantage of RNA-based aptamers that bind cell surface receptors is the possibility to be conjugated to a siRNA and used as cargoes for tissue specific internalization, we thus developed a cell SELEX based protocol to enrich for aptamers that following binding to cell surface are rapidly internalized in a receptor-mediated manner.
The whole-cell SELEX strategy holds a great promise in developing specific molecular probes for cancer biomarker discovery and for cancer diagnostic and therapeutic applications.
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 626. doi:10.1158/1538-7445.AM2011-626
Abstract 629: MEK inhibition by selumetinib (AZD6244) inhibits progression with a multicentric antiangiogenic effect and enhances the efficacy of cediranib in orthotopic human lung cancer models
Authors: Takahashi Osamu , Komaki Ritsuko , Smith Paul D. , Jürgensmeier Julian M. , Ryan Anderson J. , Bekele Benjamin N. , Wistuba Ignacio I. , Jacoby Jörg J. , Korshunova Maria V. , Biernacka Anna , Erez Baruch , Hosho Keiko , Herbst Roy S. , O'Reilly Michael S. 
Published: June 2012

Abstract
Background: Selumetinib is a potent orally available MEK 1/2 inhibitor now in clinical development. We evaluated the therapeutic efficacy of selumetinib alone or with cediranib (RECENTIN™), an orally available inhibitor of all 3 VEGFR tyrosine kinases, in distinct K-ras mutant orthotopic human non-small cell lung cancer models.
Methods: NCI-H441 or NCI-H460 cells were injected into the lungs of mice. Mice were randomized to treatment with selumetinib (12.5 or 25 mg/kg/BID po), cediranib (3 mg/kg/qd po), paclitaxel (200 µg/week ip), selumetinib + cediranib, or vehicle. When controls became moribund, all mice were sacrificed and assessed and lung tumors subjected to immunohistochemical analyses.
Results: In both models, selumetinib or cediranib were well tolerated and inhibited tumor growth and metastasis with efficacy superior to paclitaxel. The combined antitumor effects of selumetinib and cediranib were markedly enhanced with near complete metastasis suppression. Immunohistochemistry revealed that cediranib or selumetinib reduced microvessel density and tumor cell proliferation and increased apoptosis, with no effect on VEGFR2 expression. The effects were substantially enhanced when they were combined. Cediranib blocked VEGFR2 activation. Selumetinib's antiangiogenic effect, but not cediranib's, was associated with reduced VEGF expression, particularly in the H441 model. Surprisingly, selumetinib reduced tumor and endothelial VEGFR2 activation, which may in part be due to the offset of VEGF expression.
Conclusions: The combination of selumetinib and cediranib enhances their antitumor, antimetastatic, and antiangiogenic effects. Selumetinib decreased VEGF and suppressed VEGFR activation, suggesting that MEK inhibition targets VEGF-driven angiogenesis at multiple levels. These data provide a strong basis for clinical trials of selumetinib and cediranib in lung cancer.

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 629. doi:10.1158/1538-7445.AM2011-629
Abstract 648: Combined PI3K and MEK inhibition in patient-derived xenografts generated from recurrent triple negative breast cancer
Authors: Ibrahim Yasir H. , Serra Violeta , Scaltriti Maurizio , Prudkin Ludmila , Anton Pilar , Perez José , Balmaña Judit , Baselga José 
Published: June 2012

Abstract
Both the PI3K and ERK pathways have become critical therapeutic targets due to their importance in breast cancer. Some triple negative breast cancers (TNBC) are sensitive to MEK inhibition due to the presence of RAS activation signatures. However, hyperactivation of PI3K signaling through PTEN loss impairs efficacy of MEK inhibitors in TNBC. On the other hand, it is likely that inhibition of PI3K in TNBC results in compensatory feedback activation of MEK, as previously observed in HER2 positive cell-line models. Therefore, combined inhibition of both PI3K and MEK would translate to optimal therapeutic efficacy in the clinic. We generated patient-derived xenografts (PDXs) of TNBC from patients with recurrent disease to assess the efficacy of this combined therapy in a model that more closely resembles the clinical scenario.
Upon completion of informed patient consent, biopsies from patients with cutaneous, axillary or subclavicular metastases that had progressed from standard therapies were implanted in female nude mice. Five TBNC PDXs were expanded and confirmed to have equivalent pathological and morphological features as the original patient samples; they maintained similar ER, PR, HER2, PTEN and Ki67 status. Mutation status of PI3K, PTEN and RAS pathway were also evaluated. Additionally, the PTEN-loss transcriptional program and RAS-like transcriptional program were evaluated to further classify the tumors. PDXs were treated with a pan-class I PI3K inhibitor (NVP-BKM120) and a MEK inhibitor (AZD6244) as single agent or in combination. Preliminary tumor growth studies in a PDX that lacked PTEN expression demonstrated NVP-BKM120 sensitivity, but no response to AZD6244. The combination of NVP-BKM120 plus AZD6244 augmented the PI3K tumor inhibitory effect. Ongoing studies will more precisely delineate the relationship between pathway activation status and pharmacodynamic response to inhibitors targeting PI3K or MEK. These data highlight the great potential for evaluating new strategies in models that truly represent breast cancer of patients enrolling in clinical trials.
In these studies we attained data from models that faithfully resemble the disease observed in the clinic supporting the advancement of clinical trials targeting both PI3K and Ras/Raf pathways in TNBC. Since these models strongly resemble the clinical disease, PDXs can also offer new opportunities to test experimental therapies that are normally hindered by the homogeneity and culture selection of standard cell-lines.
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 648. doi:10.1158/1538-7445.AM2011-648