bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4836: Inhibition of PI3K/mTOR leads to adaptive resistance in extracellular matrix attached cancer cells
Authors: Muranen Taru E. , Selfors Laura , Worster Devin , Iwanicki Marcin , Song Loling , Morlaes Fabiana , Mills Gordon B. , Brugge Joan S. 
Published: August 2012

Abstract
The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here we show that inhibition of PI3K/mTOR in ovarian and breast cancer 3D spheroids leads to death of inner extracellular matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance to PI3K inhibitors is associated with upregulation of a cellular survival program that involves both FOXO-mediated transcription and a novel translational resistance mechanism. This program is evolutionarily well-conserved and resembles nutrient/growth deprivation, leading to translation of IRES-containing pro-survival mRNAs, previously associated with cellular stress responses. Inhibition of any of several upregulated pro-survival proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition in breast and ovarian cancer cells and ovarian cancer xenografts. These studies provide a platform for rational development of effective drug combinations through the use of 3D-based model systems together with high-throughput proteomics approaches and identify drug combinations for further analysis as cancer therapeutics.
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 4836. doi:1538-7445.AM2012-4836
Abstract 4847: CD95/Fas protects cancer cells from cell death
Authors: Hadji Abbas , Hau Annika , Peter Marcus E. 
Published: August 2012

Abstract
CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant, raising the possibility that loss of CD95 is part of a mechanism for tumor evasion. However, complete loss of CD95 is rarely seen in human cancer and many cancer cells express large quantities of CD95 and are highly sensitive to CD95-mediated apoptosis in vitro. Furthermore, cancer patients frequently have raised levels of the physiological ligand for CD95, CD95L. These data raise the possibility that CD95 could actually promote the growth of tumors through its non-apoptotic activities. We have recently shown that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth (1). Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumors. We have now generated inducible CD95 and CD95L knock down cell lines to characterize the molecular mechanisms of the dependency of cancer cells on CD95. In all cancer cells knocking down CD95 or CD95L slows down growth and in many cells causes cell cycle arrest and even cell death. In CT26L cells knock down of CD95L causes all cells to die within 2 days. This form of cell death cannot be inhibited by inhibitors of apoptosis or necroptosis and has features of mitotic catastrophe. The data suggest that CD95 maintains viability of cancer cells by preventing DNA damage. 1. Chen et al (2010) CD95 promotes tumor growth. Nature, 465, 492-496.
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 4847. doi:1538-7445.AM2012-4847
Abstract 4848: A synthetic-lethal screen identifies novel Mcl1 regulators in neuroblastoma
Authors: Laetsch Theodore , Liu Xueyuan , Sliozberg Michael , Vido Michael , Vu Annette , Goldsmith Kelly , Hogarty Michael D. 
Published: August 2012

Abstract
Neuroblastoma (NB) is a lethal pediatric tumor. Despite multimodal therapy survival remains poor due to emergent chemoresistance governed by Bcl2-homology (BH) proteins. Agents that antagonize BH proteins, such as ABT-737, are in clinical development. ABT-737 does not antagonize Mcl1, a Bcl2-homologue correlated with ABT-737 resistance in many tumors. We defined the survival bias present in NBs using functional mitochondrial profiling in response to diverse BH3 death-domain peptides. Those with a functional Bcl2-dependence were exquisitely sensitive to ABT-737 in vitro and in vivo. Those with an Mcl1-dependence were relatively ABT-737 resistant (3-5 uM IC50s), yet Mcl1 knock-down restored ABT-737 activity in this subset (nM IC50s). We therefore undertook a synthetic-lethal screen for Mcl1 regulators using siRNA against deubiquitinating enzymes (DUBs), as Mcl1 is highly regulated with a short half-life due to ubiquitin-mediated degradation and this genomic space has many plausible druggable targets. We treated Mcl1-dependent NB cell lines (IMR5 and NLF) with siRNA targeting DUBs and ABT-737 at a sublethal concentration (200 nM). This screen identified 5 targets (of 98) demonstrating synthetic lethality (Z&lt;-1.5) that was selective for Mcl1-dependent NBs. We validated these by measuring ABT-737 IC50s in vitro with and without siRNA knockdown and confirmed a &gt;10-fold decrease in IC50 for 4 of 5 targets. Three further demonstrated a &gt;10-fold decrease in ABT-737 IC50 with multiple independent siRNA supporting these as on-target effects (4/4 for PSMD14, 3/4 for PRPF8, and 2/4 for UBL5). We show that we can rescue the PSMD14 and UBL5 knock-down phenotypes by expression of an siRNA-resistant expression plasmid. While knock-down of all three targets decreases Mcl1 function, only knock-down of UBL5 (downregulates) and PSMD14 (upregulates) alter Mcl1 protein expression. We hypothesize that knock-down of PSMD14 and PRPF8 decrease Mcl1 activity through inhibitory post-translational modifications despite paradoxical or absent effects on Mcl1 protein expression, while UBL5 stabilizes Mcl1 as a ubiquitin-like PTM. Thus, we have demonstrated the robustness of a novel synthetic lethal screen to identify modulators of Mcl1 activity in vitro and identified three novel therapeutic targets regulating Mcl1 activity in NB.
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 4848. doi:1538-7445.AM2012-4848
Abstract 4909: Calcitriol and arsenic trioxide synergistically inhibited proliferation of HL-60 cell line mainly through apoptosis pathway
Authors: Bae Ji-Yeon , Kim Ji-Won , Kim Ji Yeon , Lim Yoojoo , Lee June Koo , Lee Eunyoung , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook , Kim Inho 
Published: August 2012

Abstract
Arsenic trioxide (As2O3) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia (APL). However, since not all patients could achieve complete remission after As2O3 treatment, it is necessary to investigate a novel treatment method overcoming the resistance of current treatment. However, the therapeutic role of calcitriol against APL has not yet been fully elucidated. In our study, we investigated the anti-leukemic effect of calcitriol in combination with As2O3 on the human APL cell line HL-60. Inhibition of proliferation rate of HL-60 cells was measured by the trypan blue exclusion test was resulted in dose, time- dependent expressions. To evaluate the effects of combination treatment of As2O3 and calcitriol on the cell proliferation, we analyzed the combined effects of As2O3 and calcitriol using CalcuSyn software (BioSoft, Ferguson, MO, USA), which is based on the multiple drug-effect equation of Chou and Talalay (Chou TC, et al. Adv Enzyme Regul 1984): a combination index (CI) of &lt;1, 1, or &gt;1 is defined as synergistic, additive, or antagonistic, respectively. In all combinations, the CI values calculated were less than 1. To investigate the effects of these treatments on the apoptosis pathway, we analyzed the expression of Bax, Caspase-3, Bcl-2 with the Western blot and the RT-PCR. In the Western blot analysis, lower Bcl-2 and higher Bax and Caspase-3 expressions were observed in the As2O3 or calcitriol-treated groups compared to the control group. The combination treatment decreased Bcl-2 expression and increased Bax and Caspase-3 expressions more prominently than the single treatment using either As2O3 or calcitriol. In the RT-PCR analysis, these trends were validated again with the same results. These cells were then labeled with fluorescein-conjugated Annexin V-FITC and propidium iodide (PI), and analyzed with flow cytometry to differentiate whether the main cause of cell death was apoptosis or necrosis. To resultsze, calcitriol in combination with As2O3 synergistically inhibited proliferation of the human APL cell line HL-60. In addition, calcitriol combined with As2O3 more prominently activated the apoptosis pathway than single treatment using either calcitriol or As2O3. The main cause of cell death was also apoptosis. Our results suggest that these novel findings could be applied to improve the therapeutic outcomes of patients with APL.
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 4909. doi:1538-7445.AM2012-4909
Abstract 4912: Systematic, comparative network analysis on non-small cell lung cancer
Authors: Wong Serene , Kotlyar Max , Strumpf Dan , Cercone Nick , Shepherd Frances A. , Tsao Ming-Sound , Jurisica Igor 
Published: August 2012

Abstract
BACKGROUND: Most cancers lack any effective early disease markers, prognostic and predictive signatures. We fail treating cancer due to multiple ways cancer initiates and develops treatment resistance. While drug modes of action are complex and poorly understood, using Comparative Toxicogenomics Database is an effective way to identify drug combinations. Integrating signatures with deregulated network information may lead to identifying novel treatment option for individual patients. APPROACH: A systematic graph analysis was used to extract network structure differences between normal and tumor patient samples in non-small cell lung cancer. Three gene expression datasets with 27 squamous cell carcinoma, 129 adenocarcinoma, 20 large cell carcinoma and 141 normal samples, and 18 prognostic non-small cell lung cancer gene signatures were used to construct normal and tumor co-expression graphs. RESULTS: We enumerated all 5-node graphlets in normal and tumor graphs, and separated them into 3 categories: unique for normal graph, unique for tumor graph, or present in both. We further focused on subgraphs with the same membership across all 3 datasets and unique to tumor graph. Using gene enrichment analysis with a hypergeometric test we identified 9 subgraphs significantly enriched in the term “regulation of lymphocyte activation” (p&lt;0.05), and genes related to chemokine receptors (CCR2, CCR7), interleukin (IL16), interleukin receptor (IL7R), interferon regulatory factor (IRF4), and T cells or B cells (PTPRCAP, SH2D1A, LCK, BTK, MS4A1). Importantly, this analysis identified protein interaction deregulated in tumors. Using the Comparative Toxicogenomics Database, we identified putative compounds that may “repair” the wiring of these subnetworks in tumor samples. 7 out of 7 identified compounds for the significantly up-regulated genes (p&lt;0.05), and 20 out of 25 significantly down-regulated genes (p&lt;0.05) are associated with non-small cell lung cancer. The other 5 identified compounds are known for other types of cancer or neoplasms, including lung neoplasms. Importantly, 13/38 edges have known/predicted protein interaction evidence, with a high prediction scores &gt;0.9 (11 interactions) and 0.8 (2 interactions). CONCLUSIONS: Systematic integration and network analysis of non-small cell lung signatures identifies potential treatment options and insights to the difference in the underlying wiring related to immune system, an emerging hallmark of 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 4912. doi:1538-7445.AM2012-4912
Abstract 4914: Integrated molecular profiles of primary breast tumors reveal differential interleukin signaling and improved prognostic power
Authors: Kristensen Vessela N. 
Published: August 2012

Abstract
The accumulation of high throughput molecular profiles of tumors at various levels has been a long and costly process worldwide. Combined analysis of gene regulation at various levels may point to specific biological functions and molecular pathways that are deregulated in multiple epithelial cancers and reveal novel subgroups of patients for tailored therapy and monitoring. We have collected high throughput data at several molecular levels derived from fresh frozen samples from primary tumors and matched blood from approximately 110 breast cancer patients (the MicMa dataset) with information about presence of disseminated tumor cells (DTC) and long term follow-up. The MicMa set has been used in parallel pilot studies of whole-genome mRNA expression (1), arrayCGH (2), DNA-methylation (3), whole genome SNP-CGH array (4), whole-genome miRNA expression analyses (5), TP53 mutation status dependent pathways (6) and high throughput paired-end sequencing (7). We have explored the extent to which these new profiles, acquired by molecular analyses at various levels recapitulate the initially discovered expression subclasses and their prognostic potential. Further, we attempted to integrate these by modeling mRNA, CNAs, miRNAs, and methylation in a pathway context using Paradigm (Pathway Recognition Algorithm using Data integration on Genomic Models) (8). We were able to show that combining mRNA expression and DNA copy-number leads to better discrimination of patients with respect to prognosis than any of the molecular levels studied separately. The pathways whose perturbations most strongly contributed to this classification were ERBB4, also previously found deregulated in breast and ovarian cancers, FoxM1 transcription, deregulated also in the ovarian and glioblastoma TCGA datasets, Angiopoientin receptor Tie2-mediated signaling and most notably the immune response (TCR) and interleukin signaling, IL4, IL6, IL12 and IL23 signaling. Massive interleukin signaling and similar sub-classification was observed also in DCIS (ductal carcinoma in situ) together with extracellular matrix and cell-cell adhesion regulating pathways. 1. Naume B et al. (2007) Mol. Oncol. 1, 160-171. 2. Russnes HG and Vollan HK et al. (2010) Sci. Transl. Med. 2, 38ra47. 3. Ronneberg J A et al. (2011) Mol. Oncol. 5, 61-76. 4. Van LP et al. (2010) Proc. Natl. Acad. Sci. U. S. A. 107, 16910-16915. 5. Enerly E and Steinfeld I et al. (2011) PLoS. One. 6, e16915. 6. Joshi H et al. submitted (2011). 7. Stephens P et al. (2009) Nature. 462, 1005-1010. 8. Kristensen V et al (2011)PNAS, 2001, Epub ahead
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 4914. doi:1538-7445.AM2012-4914
Abstract 4918: Modeling polymersome delivery of anticancer therapeutics
Authors: Sorrell Ian , Webb Steven D. , Shipley Rebecca J. , Hearnden Vanessa L. , Colley Helen E. , Murdoch Craig 
Published: August 2012

Abstract
Polymersomes are synthetic nano-spheres that have the potential to specifically deliver anticancer therapeutics to tumor cells. They are an ideal delivery vector because of their nanometer size, structural architecture, stealth characteristics and the ability to attach tumor-specific ligands to their outer surface. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. In this study, in vitro experimentation is used to validate a mathematical description of polymersome-mediated therapy. Mathematical predictions are given for how the properties of polymersomes (size, membrane properties) and drug load affects rates of polymersome internalisation by tumor cells and therefore treatment efficacy. This allows for an optimisation of treatment design prior to clinical development. A key focus is polymersome-drug delivery via the clathrin-mediated endocytotic pathway. We include in our theoretical description specific details of this process (including specific binding ligands, receptor clustering, ligand tether length) and show how the characteristics of receptor targeting, number of ligands per polymersome, and polymersome concentration alters its uptake by tumor cells. The theoretical model is validated against in vitro studies using polymersome drug delivery to cell monolayers derived from different tumors. Next we describe how to scale-up the model to a tissue representation of the tumor mass. In this description the concentration of solutes (including oxygen and polymersomes) are tracked throughout the tumor using computational models based on realistic tumor vascular network structures with associated blood flow that have been constructed from confocal microscopic observations of a xenograft sub-cutaneously implanted tumor. Our results quantify the dependence of polymersome uptake rate and tumor distribution on polymersome properties and dosage. This multiscale approach identifies the key polymersome properties that influence treatment outcome and enables the treatment regime to be designed specifically in response to these features.
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 4918. doi:1538-7445.AM2012-4918
Abstract 4920: Gene network models identify targets for mammary tumor normalization
Authors: Brock Amy , Li Hu , Krause Silva , Kowalski Marek , Collins James J. , Ingber Donald E. 
Published: August 2012

Abstract
The majority of breast cancer therapeutics aim at slowing tumor expansion through selective killing of tumor cells. Given the enormous plasticity of cells (highlighted by recent advances in the iPS field), we instead sought to induce a cell state transition from a mammary tumor cell phenotype to a normal mammary epithelial cell state. We have tackled the critical problem of identifying target genes for the normalization or differentiation of mammary tumor cells by employing a systems biology approach that integrates computational modeling with in vivo and in vitro studies. In vivo gene expression data of mammary tumor progression in the FVB C3(1) SV40Tag transgenic mouse model were collected at multiple time points as the disease progressed from normal gland to DCIS-like lesions to invasive carcinoma. Gene regulatory network models predicted novel transcription factor targets that appeared critical to the rise of the tumor phenotype. These putative gene targets were then assessed in a 3D spheroid assay. RNAi inhibition of two computationally predicted transcription factors reverted mammary tumor cells to a normalized mammary epithelial cell phenotype, with appropriate apical/basal polarization, lumen formation and reduced proliferative index. This integrated strategy has pinpointed transcription factors for RNAi therapeutic targeting in vivo but importantly, the method is not limited to breast cancer and may be useful for many different tumor types. In summary, our major advance has been the demonstration that a gene regulatory network reverse engineering approach can identify genes that are causatively involved in cancer progression and that represent viable therapeutic differentiation targets.
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 4920. doi:1538-7445.AM2012-4920
Abstract 4944: Crosstalk between NFκB and STAT3 in human multiple myeloma cells (U266)
Authors: Chudasama Vaishali L. , Mager Donald E. 
Published: August 2012

Abstract
Purpose: To evaluate a potential interaction between NFκB and STAT3 pathways and its consequences on treatment outcome (cell survival) in a human myeloma cell line (U266). Methods: A computational network model of signal transduction in U266 cells was used to simulate the interplay between NFκB and STAT3, suggesting that inhibition of just one of the pathways does not result in inhibition of NFκB and downstream processes, as NFκB expression is partially regulated by STAT3. To test this hypothesis, U266 cells were exposed continuously to either an IKK inhibitor (IKKi; 10 μM), a JAK inhibitor (JAKi; 10 μM), or bortezomib (Bort) (a proteasome inhibitor; 20 nM). The time-course of intracellular proteins were measured over 48 h (immunobloting), including: phospho-p65 (p-p65), p-stat3, p-IκBα, and BclXL. Cell proliferation was measured using WST-1 reagent assay kit at 72 h. PARP cleavage was measured as an indicator of apoptosis over a 24 h period. U266 cells were also exposed transiently (1 and 2 h) to Bort treatment, and the time-course of p-p65, BclXL, and PARP was measured. Results: Expression of p-p65 was unchanged following continuous exposure to IKKi and JAKi. However, p-p65 expression initially increased (1.7-fold) followed by a decrease below baseline following Bort exposure. BclXL expression remained unchanged after IKKi exposure, and it decreased (80 %) either rapidly or gradually after JAKi or Bort exposure. p-stat3 expression rapidly decreased after Bort (80 %) and was transiently increased after IKKi treatment (2 fold). For short-term Bort exposure, p-p65 expression transiently increased (2.5 fold) and then returned to baseline. BclXL expression decreased (50 %) and achieved a new steady-state baseline. Bort exposure for 2 h resulted in significant PARP cleavage (10 fold increase) in agreement with model simulations. Conclusions: Both NFκB and STAT3 pathways need to be inhibited to fully inhibit NFκB activity. Similarly, when NFκB and STAT3 are constitutively active, both transcription factors need to be inhibited to inhibit cell proliferation. Further research is needed to better understand mechanisms of p-stat3 inhibition and p-p65 transient stimulation and long-term inhibition following Bort exposure to U266 myeloma cells.
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 4944. doi:1538-7445.AM2012-4944