bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-128: The N-terminus of the ASPP2 tumor suppressor binds Ras and enhances Ras/Raf/MEK activation to promote oncogene-induced cellular senescence
Authors: Wang Zhiping , Stork Philip J. , Lopez Charles D. 
Published: June 2012

Abstract
The ASPP2 tumor suppressor is a pro-apoptotic member of a family of p53 binding proteins. It functions in part by selectively enhancing p53 transcriptional activation of pro-apoptotic target genes. Although the ASPP2 C-terminal domain binds the p53 core domain, little is known about the physical and functional interactions of other proteins to the highly structured ASPP2 N-terminus. Moreover, mounting evidence from our lab and others demonstrate that ASPP2 also mediates non-apoptotic p53-independent functions. However, the molecular mechanisms remain poorly understood. Previous reports have found that ASPP2 can localize to the cytoplasm and have identified a potential Ras-association domain in the ASPP2 N-terminus. Therefore, we wondered if novel ASPP2 functions could be mediated by ASPP2 N-terminal interaction with cytoplasmic Ras. Using co-immunoprecipitation and immunofluorescence microscopy, we identified ASPP2 in a complex with active Ras on the plasma membrane. Moreover, we also found that this interaction required the ASPP2 N-terminus since BBP, a naturally occurring alternatively spliced ASPP2 isoform lacking the N-terminus, showed markedly reduced ability to bind Ras. To determine if ASPP2 could modulate Ras function, we ectopically expressed ASPP2 in cells and found enhancement of Ras activation and subsequent stimulation of ERK phosphorylation. Conversely, ASPP2 knockdown by siRNA drastically reduced ERK phosphorylation and activation by EGF. Although it is oncogenic in tumor cells, constitutive Ras activation in normal cells leads to premature senescence in a Raf-MEK-ERK activation dependent manner. To explore if ASPP2 enhanced senescence, we knocked down ASPP2 expression with siRNA and found that senescence induced by RasV12 lentiviral infection in normal human fibroblasts was significantly attenuated. This was similar to the attenuation of senescence achieved by the MEK inhibitor PD98059. Together, our results demonstrate a novel function of the ASPP2 N-terminus in promoting cellular senescence via Ras-interaction and stimulation of Raf-MEK-ERK activity. These findings suggest a novel mechanism by which ASPP2-induced senescence may mediate its tumor suppression ability, and opens new avenues for investigation.
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 LB-128. doi:10.1158/1538-7445.AM2011-LB-128
Abstract LB-16: Inhibition of RalA as a novel strategy for targeting ovarian cancer
Authors: Farassati Faris 
Published: June 2012

Abstract
Abstract: The Ral (Ras like) GTPase guanyl nucleotide-binding proteins, RalA and RalB are direct effectors of pro-oncogene Ras. RalA and RalB are implicated in tumorigenesis and play distinct roles in mediating carcinogenesis. The critical role of RalA in the initiation and progression of ovarian cancer is entirely unclear. Here, we report that RalA is overactivated in human ovarian cancer cells and human ovarian cancer tissues. The RalA downstream effectors (RalBP-1 and CDC42) and the regulators (GalGDS, PP2A Aα and β, as well as Aurora Kinase) that modulate RalA activation during the post-translational process were found to be de-regulated in ovarian cancer cells. ShRNA-mediated knockdown of RalA inhibited ovarian cancer cell proliferation and invasion. Geranyl-Geranyl transferase inhibitors (GGTI-2147) or Aurora Kinase Inhibitor (AKI) that inhibit RalA activation at post-translational levels suppressed ovarian cancer cell growth and invasion in-vitro. Additionally, subcutaneous (SC) mouse model with these two inhibitors also showed effective inhibition of tumor growth in-vivo. Therefore, RalA is a key player in the biology and dispersal of ovarian cancer cells and is a promising target for the development of novel therapeutics. To the best of our knowledge, the role of RalA in ovarian cancer tumorigenesis has not been documented before, therefore our strategy in targeting RalA for treatment of ovarian cancer merits highly in terms of novelty.
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 LB-16. doi:10.1158/1538-7445.AM2011-LB-16
Abstract LB-160: Dual application of TLR5 agonist in cancer treatment: A single agent combines supporting care and antitumor activities
Authors: Burdelya Lyudmila , Gleiberman Anatoly , Gitlin Ilya , Aygun-Sunar Semra , Rustum Youcef , Gudkov Andrei V. 
Published: June 2012

Abstract
We have previously shown the strong radioprotective properties of TLR5 agonist flagellin in both mouse and non-human primate models (Burdelya et al., 2008, Science 320: 226–230). A pharmacologically optimized flagellin derivative, Protectan CBLB502, is currently at an advanced stage of development as a prospective radiation antidote for biodefense applications. By testing CBLB502 in combination with radiation treatment of experimental mouse tumors in vivo, we demonstrated that its tissue protection properties are limited to normal tissues with no tumor protection detected in any of numerous mouse tumor models. For example, injections of CBLB502 significantly reduced the severity of mucositis and dermatitis associated with local fractioned irradiation of the head and neck area of mice with syngeneic orthotopically grown head and neck carcinoma with no reduction of antitumor effect of experimental radiotherapy. On the contrary, use of CBLB502 led to enhanced tumor suppression by radiation and produced a detectable tumor suppressive effect even without irradiation. Similar results were obtained in s.c. grown syngeneic colon Wart tumors in rats. In this model, administration of CBLB502 reduced the severity of irinotecan-induced diarrhea, but did not interfere with the anti-tumor effect of the drug. Moreover, use of CBLB502 as a single agent had a pronounced antitumor effect in the majority of Wart tumor-carrying rats. Comparison of the effect of CBLB502 on in vivo growth of isogenic pairs of tumor cell lines differing in their TLR5 status showed that the antitumor effect of the TLR5 agonist is TLR5 dependent and is associated with tumor infiltration by immunocytes, presumably attracted following activation of TLR5 signaling in the tumor cells. Remarkably, CBLB502 caused an immunotherapeutic effect in TLR5-negative tumors growing as experimental metastases in the liver which was found to be the primary target of TLR5 agonist. The liver responds to CBLB502 injection by massive and rapid activation of NF-kB in all hepatocytes. This results in dramatic changes in the content of secreted factors, attraction of immunocytes and a strong reversible increase in liver resistance to a variety of toxic agents. Based on these results, we project clinical applications of CBLB502 as a bi-functional therapeutic agent with supporting care (protection of normal tissues from radio- and chemotherapy side effects) and immunotherapeutic activities.
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 LB-160. doi:10.1158/1538-7445.AM2011-LB-160
Abstract LB-226: Celecoxib synergizes human pancreatic ductal adenocarcinoma cells to sorafenib-induced growth inhibition involving p21 suppression
Authors: Rosendahl Ann H. , Gundewar Chinmay , Said Katarzyna , Andersson Roland 
Published: June 2012

Abstract
Purpose: The aim of this study was to evaluate the potential for combining the multikinase inhibitor sorafenib and the specific cyclo-oxygenase 2 (COX-2) inhibitor celecoxib as therapy in pancreatic adenocarcinoma cells and to test the hypothesis that a synergistic or additive effect on the Ras/MAPK/ERK and related pathways might be obtained.
Experimental design: COX-2 positive (BxPC-1) and low/negative (MIAPaCa-2, PANC-1 and AsPC-1) human pancreatic adenocarcinoma cells were exposed to sorafenib and celecoxib combined treatment in vitro, after which cell viability and various growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and Western blotting.
Results: Combined treatment with sorafenib and celecoxib resulted in synergistic inhibition of pancreatic adenocarcinoma cell proliferation through COX-2 independent mechanisms. This regimen produced combination index (CI) values between 0.67 and 0.92 for the various cell lines, suggesting significant synergistic interactions between sorafenib and celecoxib, which also markedly inhibited the migratory capacity. The growth inhibition was associated with a reduction of basal ERK1/2 activity, accumulation of cells in the G0/G1 phase of the cell cycle, induction of apoptosis and poly(ADP-ribose) polymerase cleavage. These changes were accompanied by a significant reduction of p21WAF1/Cip1 levels, where celecoxib sensitized the cells to sorafenib-mediated p21WAF1/Cip1 suppression.
Conclusion: p21WAF1/Cip1 levels are elevated frequently in human pancreatic adenocarcinoma and increases with disease progression. In this study we demonstrate that combined treatment with sorafenib and celecoxib synergistically induce growth inhibition and apoptosis through a process involving phospho-ERK1/2 and p21WAF1/Cip1 suppression. These data suggest the combined treatment of sorafenib and celecoxib as potential therapy for clinical testing in patients with pancreatic adenocarcinoma.
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 LB-226. doi:10.1158/1538-7445.AM2011-LB-226
Abstract LB-26: A mathematical methodology for determining the temporal order of pathway alterations in cancer
Authors: Cheng Yu-Kang , Beroukhim Rameen , Levine Ross L. , Mellinghoff Ingo K. , Holland Eric C. , Michor Franziska 
Published: June 2012

Abstract
Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and represent promising targets for therapeutic intervention. We have previously described a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to determine the temporal sequence of genetic alterations during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage (1). This approach was based on data of alterations in individual genes. Since specific mutational events may not be necessary to cause an oncogenic phenotype and alterations within the set of genes belonging to a particular signaling pathway may have similar or equivalent effects, we apply a pathway-based systems biology approach to the RESIC methodology. This methodology is used to determine whether alterations in specific pathways develop early or late in malignant transformation. When applied to glioblastoma multiforme copy number data from The Cancer Genome Atlas project (2), we find a consistent temporal order of common genetic alterations and the pathways to which the genes belong. These results are also consistent with experimental results that high level EGFR amplification occurs late during gliomagenesis (3–4). This extension to the RESIC methodology provides an evolutionary mathematical approach to identify the temporal sequence of pathway changes driving tumorigenesis and may be useful in guiding the understanding of signaling rearrangements in cancer development.
1. Attolini CS-O, et al. (2010) A mathematical framework to determine the temporal sequence of somatic genetic events in cancer. Proceedings of the National Academy of Sciences 107:17604–17609.
2. TCGA (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068.
3. Bachoo RM, et al. (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1(3):269–277.
4. Zhu H, et al. (2009) Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci U S A 106(8):2712–2716.
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 LB-26. doi:10.1158/1538-7445.AM2011-LB-26
Abstract LB-261: Maintenance of aerobic glycolysis provides selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl through suppression of p53 activation
Authors: Mason Emily F. , Zhao Yuxing , Goraksha-Hicks Pankuri , Coloff Jonathan L. , Gannon Hugh , Jones Stephen N. , Rathmell Jeffrey C. 
Published: June 2012

Abstract
Healthy cells require input from growth factor signaling pathways to maintain cell metabolism and survival. In contrast, cancer cells can maintain growth factor-independent glycolysis and survival through expression of oncogenic kinases, such as BCR-Abl. While disruption of these growth signals through targeted kinase inhibition can promote cancer cell death, therapeutic resistance frequently develops, and further mechanistic understanding is needed. Cell metabolism may play a central role in this cell death pathway, as we have shown that growth factor deprivation leads to decreased glycolysis that promotes apoptosis via p53 activation and induction of the pro-apoptotic protein Puma. However, it has remained unclear how cell metabolism regulates p53 activation. To investigate this, we have utilized a system in which stable overexpression of the glucose transporter Glut1 and hexokinase 1 in hematopoietic cells drives growth factor-independent glycolysis. This system allows us to examine the effects of altered glucose metabolism in the absence of other signaling events activated downstream of growth factor receptors or oncogenic kinases. Here, we extend our findings to demonstrate that elevated glucose metabolism, characteristic of cancer cells, can suppress Protein Kinase C delta-dependent p53 activation to maintain cell survival after growth factor withdrawal. In contrast, DNA damage-induced p53 activation was independent of Protein Kinase C delta and was not metabolically sensitive. Both stresses required phosphorylation of p53 at serine 18 for maximal activity, but each led to a unique pattern of p53 target gene expression, demonstrating distinct activation and response pathways for p53 that were differentially regulated by metabolism. Consistent with oncogenic kinases acting to replace growth factors, treatment of BCR-Abl-expressing cells with the kinase inhibitor imatinib led to reduced glycolysis and p53- and Puma-dependent cell death. Accordingly, maintenance of glucose metabolism inhibited p53 activation and promoted imatinib resistance. Furthermore, inhibition of glycolysis enhanced imatinib sensitivity in BCR-Abl-positive cells expressing wild type p53 but had little effect on p53-null cells. These data demonstrate that distinct pathways regulate p53 after DNA damage and metabolic stress and that inhibition of glucose metabolism may enhance the efficacy of and overcome resistance to targeted molecular cancer therapies.
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 LB-261. doi:10.1158/1538-7445.AM2011-LB-261
Abstract LB-276: Fusion transcripts in breast cancer cell lines and tumors
Authors: Thompson E. Aubrey , Asmann Yan W. , Necela Brian M. , Kalari Krishna R. , Williamson David W. , Carr Jennifer M. , Baker Tiffany R. , Schroth Gary P. , Kocher Jean-Pierre A. , Perez Edith A. 
Published: June 2012

Abstract
The role of fusion gene transcripts such as BRC-ABL1 has been long appreciated in hematopoietic malignancies. Recent evidence from next generation sequencing projects has suggested that gene fusion events and the resultant chimaeric transcripts may be expressed in solid tumors. We have developed a novel bioinformatics analytical pipeline to detect fusion gene transcripts from paired-end mRNA-seq data. The bioinformatics tool used for fusion transcript discovery employs multiple steps of false positive filtering and nominates the fusion transcript candidates with high confidence (approaching 100%). The screening and validation of the fusion candidates were quickly carried out using the recommended primer design regions as one of the outputs of the SnowShoes-FD pipeline. This pipeline was used to analyze the transcriptome of 22 breast cancer cell lines and 9 non-transformed breast cell populations. Fifty-four fusion candidates were nominated, all of which were validated using reverse transcription PCR and Sanger sequencing. Five fusion products were predicted to have a second fusion junction point between two fusion partners. These 54 fusion transcripts consist of 103 partner genes that are involved in cell cycle and/or nuclear receptor signaling. No fusion transcripts were identified from the non-transformed breast cell lines. We subsequently analyzed a panel of primary breast tumors, 8 each HER2+, triple negative, and ER+. Fifteen novel fusion transcript candidates have been nominated. Validation and functional analysis of these candidates is in progress.
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 LB-276. doi:10.1158/1538-7445.AM2011-LB-276
Abstract SY34-01: Biomarkers for predicting response to PI3K inhibitors
Authors: Cantley Lewis C. 
Published: June 2012

Abstract
Phosphoinositide 3-kinase (PI 3-kinase) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. The pathway is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism, cell growth and organism longevity. Based on deletion of genes encoding the catalytic or regulatory subunits of PI 3-kinase in the mouse, PI 3-kinase mediates insulin-dependent regulation of glucose metabolism, and defects in activation of this pathway result in insulin resistance and type 2 diabetes. In contrast, mutational events that lead to hyperactivation of PI 3-kinase result in cancers. Activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI 3-kinase or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI 3-kinase, are among the most common events in solid tumors. We, and others have generated mouse models in which a mutated form of the PIK3CA gene is expressed in a tissue-specific and reversibly inducible manner. These mice develop cancers that are dependent on continuous expression of the mutant PIK3CA gene. The PIK3CA driven tumors are FDG-PET positive and turning off PI 3-kinase with drugs results in an acute decline in FDG-PET signal that precedes tumor shrinkage. These results suggest that the ability of PI 3-kinase to stimulate high rates of glucose uptake and metabolism may be critical for the survival of PIK3CA mutant tumors.
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 SY34-01. doi:10.1158/1538-7445.AM2011-SY34-01
Abstract A26: Multi-Reg: An integrative parallel approach to uncover drivers of cancer
Authors: Akavia Uri David , Danussi Carla , Sanchez-Garcia Felix , Kotliar Dylan , Iavarone Antonio , Pe'er Dana 
Published: June 2012

Abstract
Tumor samples harbor a vast number of genomic alterations of various kinds, and it is not easy to distinguish driver alterations that contribute to oncogenesis from passenger alterations. Most computational methods attempt to identify driver alternations by focusing on the most frequent alterations. Previous work in our lab has led to the development of CONEXIC, a Bayesian framework for integrating copy number and gene expression to identify candidate driver genes in cancer and to link them to gene expression signatures they regulate (Akavia et al, Cell, 2010). This framework was applied to data from melanoma cell lines, where it correctly identified known drivers (MITF) and connected them to their known targets. In addition, it predicted novel tumor dependencies not previously implicated in melanoma, which were confirmed experimentally.
In general, current algorithms identify only one driver (the strongest) controlling a gene expression signature. However, drivers may act in parallel, where not only the strongest one is important. For example, either PTEN deletion or AKT activation can lead to a similar expression signature and phenotype. Therefore, we developed a new algorithm, based on the same principles as CONEXIC with multiple improvements. The new algorithm (called Multi-Reg) is capable of detecting multiple candidate regulators that can all act in parallel to regulate an expression signature. This algorithm can integrate mutations in addition to copy number and expression. Finally, we have designed Multi-Reg to be easier and quicker to run and more robust.
We applied Multi-Reg to glioblastoma data from The Cancer Genome Atlas (TCGA). This data includes copy number, gene expression and mutations for hundreds of primary tumor samples. We found 84 candidate regulators that were missed by CONEXIC, but discovered by Multi-Reg. Because of Multi-Reg's ability to search for genes working in parallel, it identified FGFR3, PDGFRA and NF1, in addition to EGFR & MET (identified by CONEXIC), as important candidate drivers. Additionally, Multi-Reg results identified RHPN2 as a novel oncogenic factor controlling a gene expression signature related to invasion and migration. Validation has shown that RHPN2 has limited effect on cell proliferation but induces invasiveness in glioblastoma cell lines.
Our results correctly identify known drivers of glioblastoma progression, including oncogenes such as EGFR, MET, CEBPB and tumor suppressors such as p16 and NF1. Multi-Reg also has the capability to identify more regulators than CONEXIC, and has correctly linked RHPN2 to the oncogenic phenomena it controls.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A26.