bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2826: Reversal of the basal phenotype in triple negative (TN) breast cancer using a SID decoy
Authors: Ariztia Edgardo V. , Farias Eduardo F. , Petrie Kevin , Leibovitch Boris , Zelent Arthur , Zhou Ming-Ming , Waxman Samuel 
Published: June 2012

Abstract
We have previously reported that site-specific disruption of the Sin3 complex results in targeted epigenetic reprogramming and differentiation in TN breast cancer (Farias et al., PNAS 2010, 107:11811-6). The Sin3 A/B are multidomain adapter proteins part of a multisubunit corepressor scaffold that regulates transcription via the recruitement of HDAC and BP2/JARID1 A. Sin3 (A/B) contain four paired amphipathic α-helices known as PAH domains, a central HID (HDAC interaction domain) also serves as docking platform for a variety of corepressors, a C-terminal domain is a highly conserved region. We have targeted the disruption of the PAH2 domain binding to SID (mSin3A interaction domain) containing transcription factors such as MAD1, REST, KLF-9, -10, -11, -13 and -16, using a peptide decoy containing the SID motif. These studies have been carried out in several breast cancer cell lines including 5 TN, 2 estrogen receptor positive (ER+) and a non-transformed mammary cell line.
Transfection with a plasmid expressing minimal SID or treatment with a 13 amino-acid peptide (SID peptide) disrupts transcription factor binding to the PAH2 domain resulting in extreme changes in morphology, cytoskeletal organization, adhesion, decreased extracellular proteolytic activity (MMP-9 and uPA), loss of invasive capacity and anchorage independent growth. There was re-expression of functional E-cadherin, estrogen and retinoic acid receptors. Effects in vivo xenograft also included inhibition of tumor growth and metastasis in FVB mice. 3D cultures in Matrigel have revealed a SID decoy dependent switch from a basal to a more luminal phenotype. These effects of SID decoy occurred in TN but not in ER+ or non-transformed breast cancer cell lines. Taken together, these results support the hypothesis in which SID decoy interference with PAH2 domain binding can revert Epithelial/Mesenchymal Transition in TN breast cancer cells and results in a less malignant phenotype. Fourteen candidate small molecule inhibitors, from a computerized screen of 115,000 compounds, were tested in a mammalian two hybrid assay and some of them have been tested in cellular invasion, proliferation and morphogenesis assays. One of them, compound 14 (C14) has shown no toxicity, induces E-cadherin expression and is effective in inhibiting Matrigel invasion of MDA-MB-231 at 100 nM.
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 2826. doi:10.1158/1538-7445.AM2011-2826
Abstract 2829: Preclinical characterization of TKM-080301, a lipid nanoparticle formulation of a small interfering RNA directed against polo-like kinase 1
Authors: Semple Sean C. , Judge Adam D. , Robbins Marjorie , Klimuk Sandra , Eisenhardt Merete , Crosley Erin , Leung Ada , Kwok Raymond , Ambegia Ellen , McClintock Kevin , MacLachlan Ian 
Published: June 2012

Abstract
Small interfering RNAs (siRNAs) have tremendous potential for the selective inhibition, or ‘silencing’, of genes involved in cancer cell growth and division. This inhibition occurs through a process known as RNA interference (RNAi). Polo-like kinase 1 (PLK1) is a target that has multiple critical roles in cell cycle regulation and cytokinesis. Here we describe the preclinical characterization of TKM-080301, a lipid nanoparticle (LNP) formulation of an siRNA directed against human PLK1 mRNA. Studies were performed to assess the in vitro pharmacologic activity and inherent immune stimulatory potential of various siRNAs. PLK1 siRNA formulated in LNP resulted in potent anti-proliferative activity and gene-specific silencing in many cancer cell lines; and TKM-080301 exhibited strong anti-tumor activity in several xenograft models of human cancer, including tumors implanted intra-hepatically and subcutaneously. RNAi and the intended pharmacologic effects were confirmed in these models by histopathology, to visualize mitotic disruption, and by molecular methods, to confirm the presence of the RNAi-induced PLK1 mRNA cleavage product, the degree of PLK1 silencing relative to housekeeping genes, and the duration of silencing. In vivo, PLK1 silencing persisted for up to 7-10 days after a single administration and, importantly, occurred in the absence of any measurable stimulation of the innate immune system. Finally, unlike most small molecule PLK1 inhibitors, which are highly myelosuppresive, the toxicity profile of TKM-080301 was governed by the distribution profile of the LNP and toxicity was largely restricted to the liver and spleen. Collectively, these studies support the clinical evaluation of TKM-080301 as a new approach to targeting PLK1 in solid 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 2829. doi:10.1158/1538-7445.AM2011-2829
Abstract 2836: Rapamycin prolongs overall survival and progression-free survival in a mouse model of lung cancer in never smokers resistant to erlotinib
Authors: Kawabata Shigeru , Mercado Jose , Hollander M. Christine , Wilson Willie , Regales Lucia , Pao William , Janne Pasi A. , Wong Kwok-Kin , Dennis Phillip A. 
Published: June 2012

Abstract
Lung cancer in never smokers accounts for approximately 25,000 cases/yr in the US, and is characterized by distinct molecular alterations such as mutations in EGFR. Despite initial responses to EGFR inhibitors such as erlotinib, tumors invariably recur with selection of tumor cells that have mutations in EGFR that confer resistance. Previously we showed that rapamycin, an inhibitor of mTOR, could inhibit tobacco carcinogen-induced lung tumorigenesis. Here, we used an inducible, genetically engineered mouse model of lung cancer in never smokers resistant to erlotinib (CC10-rtTA, EGFRL858R/T790M) to test whether rapamycin could prevent lung tumorigenesis. Prior to detection of tumors, mTOR was activated in lung tissues by the mutant EGFR transgene. When given to achieve trough drug levels achievable in humans, rapamycin decreased tumor incidence by 52% compared to vehicle at 8 wk, as assessed by microCT. Rapamycin increased overall survival by more than 3 fold (HR=0.075, p&lt;0.0001), which was dependent upon continued rapamycin treatment. To extend these studies, we treated mice with a new irreversible EGFR TKI, WZ4002, and randomised them to consolidation treatment with rapamycin or vehicle. Mice treated with rapamycin had increased progression-free survival and overall survival (p = 0.014 and 0.0007, respectively). Tumors from mice that progressed on rapamycin continued to show inhibition of mTOR, with no evidence of feedback activation of Akt. In a series of 7 resected human NSCLC specimens with T790M mutations, 7/7 displayed increased mTOR activation, highlighting the potential clinical application of rapamycin as a chemopreventive agent in EGFR-driven 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 2836. doi:10.1158/1538-7445.AM2011-2836
Abstract 284: Aspirin, NSAIDs, statins and risk of lung cancer: Gene by drug interaction
Authors: Chun EunMi , Lee Mi-Sun , Asomaning Kofi , Wain John C. , Heist Rebeccal , Su Li , Christiani David C. 
Published: June 2012

Abstract
Lung cancer remains the leading cause of cancer-related mortality. Chemoprevention strategies have been developed to prevent lung cancer. Epidemiologic studies have shown that use of chemopreventive drugs may decrease cancer risk due to their pleiotropic effects. However, the effects of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and statins use have not been examined in terms of lung cancer. Therefore, we aimed to investigate the effects of aspirin, NSAIDs, and statins use on reduction in the risk of lung cancer. We further examined whether genetic polymorphisms in several metabolic pathway genes modify these effects. The study population consisted of 1,582 lung cancer patients and 816 controls from the Massachusetts General Hospital (MGH). Controls were recruited from healthy friends and non-blood related family members, usually spouses of lung cancer cases or of other cases of from the cardiothoracic service. of several groups of hospital patients. SNPs were assessed in genes involved in phase II (GSTs, NAT2, EPHX, and NQO1), DNA repair (ERCC1, ERCC2, and XRCC1), DNA methylation (MTHFR C677T and A1298C), and angiogenesis (VEGF +936C&gt;T, -460T&gt;C, and +405G&gt;C) pathways. We used logistic regression models to estimate the odds ratios (OR), adjusting for covariates including age, gender, smoking status, and pack-years. After adjustment for covariates, the use of statins and aspirin were significantly associated with a lower risk of lung cancer [OR 0.74, 95% confidence interval (CI) 0.56 to 0.97 for statins and OR 0.36, 95% CI 0.27 to 0.47 for aspirin, respectively], whereas an opposite effect was seen with NSAIDs. Significant effect modifications were found by NQO1 gene polymorphisms with the use of statins (OR 0.57, 95% CI 0.40 to 0.80 for CC versus OR 1.21, 95% CI 0.74 to 1.99 for CT or TT, P for interaction = 0.03) and by GSTP1 with aspirin use (OR 0.23, 95% CI 0.15 to 0.35 for AA versus OR 0.46, 95% CI 0.32 to 0.67 for AG or GG, P for interaction = 0.04). Our results indicate that statins and aspirins use may attenuate in the risk of lung cancer and genetic polymorphic genes may modify these associations. Further large scale studies are needed to confirm our findings and to screen for other genes that modify the relation.
Supported by NIH grants CA704386, CA92824, and CA90578.
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 284. doi:10.1158/1538-7445.AM2011-284
Abstract 2842: CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis
Authors: Qian Binzhi , Li Jiufeng , Zhang Hui , Zhang Jinghang , Snyder Linda A. , Pollard Jeffrey W. 
Published: June 2012

Abstract
Macrophages are abundant in the tumor microenvironment and enhance malignancy through their promotion of angiogenesis and invasion at the primary tumor site as well as extravasation, target organ seeding and persistent growth at distant metastatic sites. To determine the origin and recruitment of tumor associated macrophages, different populations of monocytes were FACS sorted and adoptively transferred into mice bearing MMTV-PyMT induced mouse mammary tumors with or without spontaneous pulmonary metastases. Ly6C+ inflammatory monocytes were preferentially recruited to pulmonary metastases but not primary tumors in a CCL2 (also known as MCP1) dependent manner. Human inflammatory monocytes were also preferentially recruited to pulmonary metastases of human breast cancer cells in immuno-compromised mice in a CCL2 dependent manner. These inflammatory monocytes promote tumor cell trans-endothelial migration in vitro, a process that is abrogated by an anti-CCL2 neutralizing antibody. Neutralizing CCL2 in vivo blocks the recruitment of metastasis associated macrophages and their direct interaction with metastasizing tumor cells, leading to inhibition of tumor cell extravasation and metastatic seeding. Inhibition of tumor cell-derived CCL2 inhibits their metastatic seeding. Secretory factors from inflammatory monocytes were identified to mediate their metastasis-promoting function in vitro and in vivo. Both CCL2 expression and macrophage infiltration are correlated with poor prognosis in human breast cancer. Our data strongly suggest that recruitment of Ly6C+ inflammatory monocytes is the mechanistic link between these two clinical associations and suggests new therapeutic targets for treating metastatic breast disease.
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 2842. doi:10.1158/1538-7445.AM2011-2842
Abstract 2869: Activation of AMP-activated protein kinase(AMPK) enhances Radiosensitization via inhibition of mTOR pathway in Rapamycin-resistant non-small cell lung cancer cells
Authors: Woon Kim Kwang , Kwang Jung Dae , Lu Bo 
Published: June 2012

Abstract
Purpose: Most drug resistance cancer cells have resisted to radiation therapy. In this study, we hypothesized that inhibition of mammalian target of rapamycin(mTOR) via activation of AMPK could potentially enhance radiosensitization in Rapamycin-resistant non- small cell lung cancer stem cells.
Methods: Stem cell marker was detected with CD133 and ALDH antibodies. P-AKT, P-mTOR and P-S6R were detected by Western Blotting. Clonogenic assay was used to determine radiosensitivity. Apoptosis was measured using the Annexin V-fluorescent isothiocyante apoptosis detection kit I (Pharmingen) with flow cytometry in vitro, and cleaved capase 3 by Western botting. Autophagy was determined by punctuate localization of GFP-LC3 fusion protein, which observed under a confocal fluorescence microscope in vitro. ATP levels were measured using Bioluminescence Assay kit CLS II from Roche Scientific (Indianpolis, IN, USA) as per the manufacturer's protocol.
Results: Level of CD133 and ALDH expression which are markers of stem cell, P-Akt, p-mTOR and P-S6R proteins were enhanced in Rapamycin-resistant non- small cell lung cancer stem cells (CSNSCLCSTC) when compared to parental non-small cell lung cancer (H460) cells. Rapamycin-resistant non- small cell lung cancer stem cells mediate less radiation sensitivity when compared with parental cells in clonogenic assay(DER=0.82, p=0.02). However Metformin, activator of AMPK, obviously enhanced sensitivity of Rapamycin-selected non- small cell lung cancer stem cells to radiation (DER=1.2, p=0.01). Therefore, this enhanced radiosensitization was associated with a downregulation of mTOR signaling pathway and an increase in characteristic punctuate localization of GFP-LC3 as a marker for autophagy.
Conclusions: These findings may be utilized as a novel strategy to enhance radiation therapy in drug-selected non-small cell lung cancer stem cells.
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 2869. doi:10.1158/1538-7445.AM2011-2869
Abstract 2885: The NCI-Nature Pathway Interaction Database: A comprehensive resource for cell signaling information
Authors: Anthony Kira , Skinner Mhairi A. , Buchoff Jeffrey R. , McCarthy Nicola , Schaefer Carl F. , Buetow Kenneth H. 
Published: June 2012

Abstract
The NCI-Nature Pathway Interaction Database (PID, http://pid.nci.nih.gov) is a freely available collection of professionally curated and expert-reviewed signaling and regulatory pathways composed of human molecular interactions and cellular processes extracted from the primary literature. As of November 2010, the database contains 116 pathways and networks encompassing 7810 interactions, 3531 proteins, 137 small molecules, 3101 complexes, 5930 peer-reviewed publications and more than 10500 uses of evidence codes, and includes recent additions to the Notch and Wnt pathways along with the AP1 network. Created in a collaboration between the U.S. National Cancer Institute and Nature Publishing Group, the PID offers a range of tools to facilitate pathway exploration. Users can browse pathways and create network maps based on molecule or biological process queries; interactive network maps are displayed in JPG, SVG and Silverlight formats. The Batch query tool allows users to overlay molecule lists, such as those derived from microarray data, onto pathways. Users can also download a list of references used to create the pathway, pathway molecule lists, and complete database content in extensible markup language (XML) or Biological Pathways Exchange (BioPAX) Level 2 or Level 3 formats. The database is updated every month and supplemented by a concise editorial section that provides synopses of recent noteworthy papers in cell signaling and specially commissioned articles on the practical uses of other relevant Biomedical Informatics tools. Users can sign up for email alerts or RSS feeds to receive database content updates.
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 2885. doi:10.1158/1538-7445.AM2011-2885
Abstract 2898: Inhibition of heat shock protein 90 through HSP990 causes cell cycle arrest, growth inhibition, and apoptosis in glioblastoma tumors
Authors: Shrivastav Meena , Ostrem Jamie , Schroeder Mark M. , Carlson Brett L. , Sarkaria Jann N. 
Published: June 2012

Abstract
Heat shock protein (HSP) 90 is a molecular chaperone that modulates stability of several client proteins, many of which are key regulators of signaling pathways in glioblastoma multiforme (GBM). The potential for simultaneously targeting multiple effectors makes HSP90 an appealing therapeutic target. Here, we evaluated the biological activity of HSP990, a novel HSP90 inhibitor (Novartis Pharma AG) in a panel of adult glioma primary xenograft lines (n=15). HSP990 treatment resulted in a dose-dependent growth inhibition with IC50 values in the low nM range in each of the primary lines. HSP990 caused G2/M cell cycle arrest and apoptosis-induction within 72 hours of treatment. In addition, treatment with HSP990 resulted in up-regulation of HSP70, and decrease in activity of client proteins AKT, CDC2, CDC25C and activation of caspase 8 and 3, in tested cell lines. A range of sensitivity based on EGFR status was observed. EGFR-amplified cells showed depletion of client proteins and growth inhibition at lower dose of HSP990 (10nM) than wildtype EGFR cells (30nM). Furthermore, neurosphere formation assays revealed that HSP990 was effective against the growth of glioblastoma stem cells (GSCs) in 6 tested glioblastoma xenograft lines (IC50 less than 10nM).These results suggest that that both cell cycle effects and induction of apoptosis are mechanisms governing HSP990 activity against glioblastoma. Further studies are warranted to characterize the mechanisms by which HSP990 exerts its anti-glioma effects which in turn may provide valuable insights in developing HSP990 as a novel personalized GBM treatment based on specific molecular signatures.
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 2898. doi:10.1158/1538-7445.AM2011-2898
Abstract 2917: Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma
Authors: Einspahr Janine G. , Calvert Valerie S. , Alberts David S. , Curiel-Lewandrowski Clara , Warneke James , Stratton Steven P. , Liotta Lance , Pellacani Giovanni , Krouse Robert , Prasad Anil , Deng Jianghong , Bowden Timothy , Petricoin Emanuel F. 
Published: June 2012

Abstract
In order to identify important cell signaling derangements in squamous cell carcinoma (SCC) and its precursor actinic keratosis (AK) as a means to uncover important molecular targets and further characterize this disease, we analyzed two independent tissue study sets using Reverse Phase Protein Microarrays (RPMA). Set 1 served as a pilot as well as a means to generate candidate pathway alterations that could be further validated in a second independent sample set. Study Set 1 was comprised of 4 AK, 6 advanced SCC (≥ 2 cm), 7 non-advanced SCC, and 20 normal appearing skin samples [upper-inner arm, (UIA)]. Set 2 included15 AK, 5 advanced SCC, 4 non-advanced SCC and 20 UIA. LCM was used to isolate pure populations of epithelial cells. Fifty-one key signaling proteins and phosphorylated proteins were assessed for set 1 showing that the MEK-ERK pathway was activated in SCC compared to AK and normal skin, that EGFR was aberrantly activated in SCC, and that the mTOR pathway was highly activated in SCC. Unsupervised clustering revealed dramatic differences in SCC signaling architecture. Statistical analysis (p&lt;0.01) found that pro-survival signaling through phosphorylation of ASK, and 4EBP1 as well as increased Bax and Bak expression were higher in AK vs UIA. We then expanded our pathway network activation mapping in set 2 to 108 key signaling proteins. We corroborated the MEK-ERK, EGFR and mTOR pathway activation and identified an expanded number of upstream and downstream signaling molecules within these pathways, and that SCC is indeed a pathway activation-driven disease.
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 2917. doi:10.1158/1538-7445.AM2011-2917
Abstract 2929: MAP/MEK pathway inhibitors reduce cell viability of canine hemangiosarcoma primary cells
Authors: Andersen Nicholas , Boguslawski Elissa , Froman Roe , Blanski Alexander , Zaida Rida , Smith Josh , Dykema Karl , Furge Kyle , Duesbery Nicholas ,   Canine Hereditary Cancer Consortium
Published: June 2012

Abstract
Angiosarcoma is a rare endothelial derived soft-tissue tumor with an estimated incidence of 0.2/100,000 persons/year. Current treatment regimes include surgical resection followed by chemotherapy. Even after treatment, reoccurrence is likely and usually fatal. The canine equivalent of angiosarcoma, hemangiosarcoma (HSA), is a relatively common canine endothelial neoplasm with an overall incidence of 24/100,000. In addition, canine HSA is more prevalent in specific breeds suggesting a genetic component. Similar to human angiosarcoma, HSA present as two basic forms: visceral (spleen or cardiac) and dermal. Furthermore, canine HSA occur spontaneously making canine HSA a relevant model system to study human angiosarcoma. Interestingly, MEK/MAPK signaling cascade is activated in Kaposi's Sarcoma, another human endothelial derived cancer. We hypothesize that the MEK/MAPK signaling cascade is vital for HSA and angiosarcoma growth and survival. We performed expression analysis supplemented by small molecule inhibitor studies utilizing canine primary cell isolates derived from visceral and dermal HSA. MAPK pathway expression signatures are elevated in HSA primary isolates compared to proliferating endothelial cells. Consistent with mRNA expression studies, ERK2 is constitutively phosphorylated in serum starved conditions. In addition, HSA cell viability is reduced by the MEK1/2 inhibitor CI-1040 compared to isolated canine endothelial cells. Other inhibitors targeting tyrosine kinase receptors (Sorafenib, EGFR Inhibitor, and SU11652) also decrease HSA cell viability. We conclude a network of tyrosine kinase receptors constitutively activate the MEK/MAPK signaling pathway in HSA. This work provides insights in the etiology and therapeutic potential for targeting both canine HSA and angiosarcoma.
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 2929. doi:10.1158/1538-7445.AM2011-2929