bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2805: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma
Authors: Varela Ignacio , Tarpey Patrick , Raine Keiran , Huang Dachuan , Ong Choon Kiat , Stephens Philip , Davies Helen , Jones David , Lin Meng-Lay , Teague Jon , Bignell Graham , Butler Adam , Cho Juok , Dalgliesh Gillian L. , Galappaththige Danushka , Greenman Chris , Hardy Claire , Jia Mingming , Latimer Calli , Lau King Wai , Marshall John , McLaren Stuart , Menzies Andrew , Mudie Laura , Stebbings Lucy , Largaespada David A. , Wessels L.F.A. , Richard Stéphane , Kahnoski Richard J. , Anema John , Tuveson David , Perez-Mancera Pedro , Mustonen Ville , Fischer Andrej , Adams David J. , Rust Alistair , Chan-on Waraporn , Subimerb Chutima , Dykema Karl , Furge Kyle A. , Campbell Peter J. , Teh Bin Tean , Stratton Michael R. , Futreal P. Andrew
Published: June 2012

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (KDM6A), JARID1C (KDM5C) and SETD2. These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodeling complex gene PBRM1 as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

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 2805. doi:10.1158/1538-7445.AM2011-2805
Abstract 281: Prevalence of Human papilloma virus in oral squamous cell carcinoma using Liner Array HPV genotyping kit
Authors: Ohno Keisuke , Sugahara Keisuke , Katakura Akira , Kawachi Homare
Published: June 2012

Background. The major risk factors for oral squamous cell carcinoma (OSCC) are cigarette smoking, alcohol consumption, and betel quid chewing. In addition, human papillomavirus (HPV) infection has been associated with some OSCC. However, the relationships of HPVs to OSCCs remain unclear because of the difficulties in interpreting studies that demonstrate various prevalence rates of HPVs. We examined the prevalence of HPV in OSCCs. For HPV detection and genotyping, a sensitive and specific PCR-based method, the Roche Linear Array HPV genotyping kit test was used for these studies.

Materials and Methods. Forty-five Japanese patients with OSCC were included in the present study. Surgical resection of primary tumors and normal tissues from all patients was performed at the Hospital of Tokyo Dental College, between December 2007 and December 2010. We assessed HPV infection in OSCC patients using the Roche Liner Array HPV genotyping Test, which can detect 37 different HPV types.

Results. HPV was detected in 9 OSCC patients (20%). HPV subtype 39, 42 was the most prevalent type, but other types detected included 31, 33, 45 . . . high-risk types and 3, 6, 8 . . . low-risk types.

Conclusion. The Roche Liner Array HPV genotyping Test is currently used as a standardized diagnostic test for HPV detection in cervical carcinoma in Europe. Some studies have shown that the most prevalent HPV subtype was the high-risk type HPV-16, However we showed that HPV is detected multiple type involved low- and high-risk type in oral carcinoma. We suggested that multiple subtypes of HPV implicated OSCC.

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 281. doi:10.1158/1538-7445.AM2011-281
Abstract 2811: GPC1 promotes tumor growth and angiogenesis in a KrasG12D- Driven mouse model of pancreatic cancer
Authors: Whipple Chery A. , Korc Murray
Published: June 2012

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy that is highly therapy-resistant and is the fourth leading cause of cancer-related deaths. The poor prognosis is due, in part, to late diagnosis in conjunction with a high frequency of activating Kras mutations, a loss of the tumor suppressor genes p16INK4A/p14ARF, as well as an over-abundance of heparin-binding growth factors (HBGFs) and their co-receptors. Glypican-1 (GPC1), a co-receptor required for efficient signaling by heparin-binding growth factors, is overexpressed in PDAC and plays a critical role in cell growth, metastasis, and angiogenesis of human and mouse cancer cells. While it is known that the loss of GPC1 results in decreased tumor growth and metastasis in orthotopic mouse models, GPC1's role in pancreatic tumor initiation, development, and progression is unknown. Accordingly, we generated a GPC1 null mouse that combines pancreas-specific Cre-mediated activation of oncogenic Kras (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. Loss of GPC1 resulted in attenuated pancreatic tumor growth and invasiveness, as well as decreased angiogenesis, cancer cell proliferation, and mitogen activated protein kinase (MAPK) activation. These differences were first observed in 30 day old mice and were still highly significant in 65 day old mice. Moreover, pancreatic cancer cells isolated from the tumors of GPC1 null mice were not as invasive in response to fibroblast growth factor 2 (FGF2) as cancer cells isolated from wild-type mice. These data demonstrate in a genetic mouse model of PDAC that GPC1 does not contribute to pancreatic cancer initiation, but that even in the presence of two highly prevalent molecular alterations (oncogenic Kras and loss of p16) endogenous GPC1 contributes to PDAC progression by facilitating tumor growth, angiogenesis, and invasion. Our findings support the concept that GPC1 may be a therapeutic target in PDAC.

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 2811. doi:10.1158/1538-7445.AM2011-2811
Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling
Authors: Bender Mark H. , Hipskind Philip A. , Capen Andrew R. , Cockman Michael , Credille Kelly M. , Gao Hong , Bastian Jolie A. , Clay Julia M. , Lobb Karen L. , Sall Daniel J. , Thompson Michelle L. , Wilson Takako , Wishart Graham N. , Patel Bharvin K.R
Published: June 2012

The Hedgehog (Hh) pathway is a highly conserved signaling system that plays an important role in embryonic development and tissue homeostasis through regulation of cell differentiation and proliferation, and deregulated Hh signaling has been implicated in variety of cancers. Two distinct mechanisms are responsible for inappropriate and uncontrolled Hh pathway activation in human malignancies: ligand-dependent, due to over-expression of Hh ligand, and ligand-independent, resulting from genetic mutations in pathway components such as Patched (Ptch) and Smoothened (Smo). Smo, a member of the class F G-protein coupled receptor family, is a key regulator of Hh signaling pathway, and therefore is an attractive target for pathway modulation. We have identified a potent and selective small molecule antagonist of Smo. This novel molecule (LY2940680) binds to the Smo receptor and potently inhibits Hh signaling in Daoy, a human medulloblastoma tumor cell line, and C3H10T½, a mouse mesenchymal cell line. Importantly, LY2940680 binds to and inhibits the functional activity of resistant Smo mutant (D473H) produced by treatment with GDC-0449 (a Smo antagonist from Genentech). LY2940680 also has excellent pharmacokinetic properties in rodent and non-rodent species. Treatment of Ptch+/− p53−/− transgenic mice, which spontaneously develop medulloblastoma, with oral administration of LY2940680 produced remarkable efficacy and significantly improved their survival. Magnetic resonance imaging of these mice revealed rapid kinetics of anti-tumor activity. Immunohistochemistry analysis of medulloblastoma tumors showed that LY2940680 treatment induced Caspase-3 activity and reduced proliferation. LY2940680 inhibited Hh regulated gene expression in the subcutaneous xenograft tumor stroma and produced significant anti-tumor activity. In summary, we have characterized an orally bio-available small molecule Smo antagonist that may provide therapeutic benefit to cancer patients with deregulated Hh signaling.

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 2819. doi:10.1158/1538-7445.AM2011-2819
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

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

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

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<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

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>T, -460T>C, and +405G>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

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

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

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

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

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<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

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
Abstract 2932: Role of P53 in the negative regulatory function of PIAS3 with STAT3 in lung cancer
Authors: Dabir Snehal , Kluge Amy , Dowlati Afshin
Published: June 2012

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) and p53 mutations both play an important role in lung cancer pathogenesis. We have demonstrated a negative inhibitory role of Protein Inhibitor of Activated STAT3 (PIAS3) in STAT3 signaling (Kluge et al 2009 and Dabir et al. 2009) in lung cancer. Recent data suggests that p53 plays a role in oncogenic STAT3 signaling. We sought to determine the biochemical interaction between PIAS3, STAT3 and p53 at both protein and DNA levels in p53 wild-type (A549 and H1666), mutant (Calu1) and p53 null (H358) non-small cell lung cancer (NSCLC) lines. We demonstrate that PIAS3 binds to STAT3 under Epidermal Growth Factor (EGF) stimulation in p53 WT cell lines but not so significantly in p53 mutant cell lines. ChIP studies with PIAS3 antibody showed p53/PIAS3 binding to DNA under EGF stimulation. We observed in vivo binding of PIAS3 to the promoter region of RNSP1 (target of p53) in A549 (p53 WT) cells by Promoter Tiling Array. Our initial data suggests that PIAS3 negative regulatory effect on STAT3 is more prominent in p53 WT cells. Indeed, transfection of WT cells with a PIAS3 construct results in a significant decrease in STAT3 transcriptional activity in all cells but more significantly in WT cells. Knockdown of p53 using sh-p53 lentivirus construct tagged with GFP in p53 WT cells shows that it partially negates the effects of PIAS3 on STAT3 suggesting at least a partial requirement of WT p53 for full PIAS3 effects on STAT3 signaling. However our data suggests that PIAS3 induces apoptosis as demonstrated by TUNEL assay and changes of Bcl2 family members irrespective of p53 status suggesting that its growth inhibitory effects are p53 independent.

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 2932. doi:10.1158/1538-7445.AM2011-2932
Abstract 2936: MicroRNA-205 interdiction of Src-mediated oncogenic pathways in renal cancer
Authors: Majid Shahana , Dar Altaf A. , Saini Sharanjot , Hirata Hiroshi , Shahryari Varahram , Tanaka Yuichiro , Yamamura Soichiro , Ueno Koji , Zaman Mohd Saif , Singh Kamaldeep , Chang Inik , Deng Guoren , Carroll Peter R. , Dahiya Rajvir
Published: June 2012

Introduction and Objective: The Src family of protein kinases (SFKs) plays key roles in regulating fundamental cellular processes, including cell growth, differentiation, cell shape, migration and survival, and specialized cell signals in various malignancies. The pleotropic functions of SFKs in cancer make them promising targets for intervention. We investigated the role of miR-205 in inhibition of Src-mediated oncogenic pathways in renal cancer.

Methods: The methods employed in this study include quantitative-real time PCR; western blot; fluorescence-activated cell sorting assays for cell cycle distribution and apoptosis; assays for cell viabiltity, clonability, migration and invasiveness of prostate cancer cells. Luciferase reporter and mutational assays; generation of miR-205 stable cells and in-vivo study in nude mice was also performed.

Results: The expression of miR-205 was significantly suppressed in renal cancer cell lines and tumors when compared with normal tissues and a non-malignant cell line, and is correlated inversely with the expression of SFKs. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3’UTR sequences complementary to either Src, Lyn or Yes, which was abolished by mutations in these 3’UTR regions. Over-expression of miR-205 in A498 cells reduced Src, Lyn and Yes expression both at mRNA and protein levels. Proliferation of renal cancer cells was suppressed by miR-205, mediated by the phosphoSrc-regulated ERK1/2 pathway. Cell motility factor- FAK and STAT3 activation was also inhibited by miR-205. Transient as well as stable over-expression of miR-205 in A498 cells resulted in induction of G0/G1 cell cycle arrest and apoptosis as indicated by decreased levels of cyclin D1 and cMyc, suppressed cell proliferation, colony formation, migration, and invasion in renal cancer cells. miR-205 also inhibited tumor cell growth in vivo. This is the first study demonstrating that miRNA-205 inhibits proto-oncogenic Src family of kinases indicating a therapeutic potential of miR-205 in the treatment of renal cancer.

Conclusion: This study demonstrates that miRNA-205 inhibits proto-oncogenic Src family of kinases indicating a therapeutic potential of miR-205 in the treatment of renal 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 2936. doi:10.1158/1538-7445.AM2011-2936
Abstract 2939: Chk1 inhibition and Wee1 inhibition combine synergistically to inhibit cellular proliferation
Authors: Davies Kurtis D. , Sullivan Francis , von Carlowitz Ira , Huerou Yvan Le , Wallace Eli , Woessner Richard D. , Gross Stefan
Published: June 2012

Inhibition of the checkpoint kinase Chk1, both as a monotherapy and in combination with DNA damaging cytotoxics, is a promising therapeutic strategy for human cancer. However, much remains to be learned in regard to the patient populations that will respond best to a Chk1 inhibitor and the optimal therapeutics to combine with a Chk1 inhibitor. In an effort to discover sensitizing mutations and novel combination strategies for Chk1 inhibition, we performed a synthetic lethality siRNA screen with the selective Chk1 inhibitor Chk1-A. This screen employed a custom made library of siRNAs against 197 genes (3 siRNAs per gene), most of which are involved in cell-cycle control or DNA damage repair. One of the most prominent and consistent hits across runs of the screen performed in PC3, LNCaP, and A549 cell lines was Wee1 kinase. MK-1775 is a small molecule inhibitor of Wee1 that is currently in early stage clinical trials. In confirmation of the results obtained from the siRNA screen, we found that Chk1-A and MK-1775 synergistically inhibited proliferation in multiple cell types. The combination of the two molecules resulted in up to a 5-fold enhancement of anti-proliferative activity compared to what would be expected from pure additivity. This anti-proliferative synergy correlated with a synergistic induction of apoptosis. We explored the mechanism of the impressive synergy by examining the cellular and biochemical effects of the Chk1-A and MK-1775 combination. We found that co-treatment with the two inhibitors resulted in dramatic decreases in inhibitory phosphorylation of cyclin-dependent kinases 1 and 2, increases in DNA damage, and the collapse of DNA replication. In conclusion, the combination of a Chk1 inhibitor and a Wee1 inhibitor may be an effective treatment strategy for 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 2939. doi:10.1158/1538-7445.AM2011-2939
Abstract 2943: Targeting the E2F pathway in cancer chemotherapeutics
Authors: Kurtyka Courtney A. , Ma Yihong , Bian Haikuo , Cubitt Christopher , Law Brian , Corsino Patrick , Cress W. Douglas
Published: June 2012

HLM006474 is a recently identified small molecule E2F inhibitor. Since E2F is known to drive expression of genes required for cell cycle progression, it is predicted that blocking the E2F pathway will slow proliferation and have anticancer activity. Microarray analysis demonstrates that HLM006474 treatment results in profound changes in the expression of genes involved in cell cycle progression and nucleotide biosynthesis. Flow cytometry reveals that treatment of A375 cells results in a cell cycle arrest, primarily in G2/M. As would be expected, cell lines deficient in Rb are more sensitive to E2F inhibition than are syngeneic lines expressing Rb. HLM006474 reduces the proliferation of a broad array of cell lines with a biological IC50 that varies between 5 and 70 μM. Combination of HLM006474 with common chemotherapeutic agents cisplatin and gemcitabine demonstrate little synergy; however HLM006474 synergizes with paclitaxel and a novel cdk inhibitor NSC11702. Interestingly, we discovered that paclitaxel sensitivity inversely correlated with E2F4 levels in a series of non-small cell lung cancer (NSCLC) lines, suggesting that synergy between HLM006474 and paclitaxel is due to HLM006474's inhibition of E2F4 activity and expression. To test this, H1299 cells which have high E2F4 levels and a high paclitaxel IC50 were depleted of E2F4 with siRNA and the IC50 determined. Taken together, these results suggest that HLM006474 may have efficacy against cancers in which E2F is deregulated and may be useful in combination with other drugs that target cell cycle components.

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 2943. doi:10.1158/1538-7445.AM2011-2943
Abstract 295: Detection of hypomethylation of LINE1 on peripheral white blood cells and plasma DNA in US hepatocellular carcinoma patients
Authors: Zhang Yujing , Delgado-Cruzata Lissette , Wu Hui-Chen , Gamble Mary , Wang Qiao , Regina Santella M. , Siegel Abby B.
Published: June 2012

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is increasing in the United States. Epigenetic changes, including genomic DNA hypomethylation, have been implicated in cancer development by inducing chromosomal instability. In the present study, methylation of long interspersed nucleotide element-1(LINE1), a surrogate marker of global hypomethylation, in peripheral white blood cells and plasma DNA in 47 US HCC patients was detected by pyrosequencing. Correlations between LINE1 methylation, and clinical data and other biomarkers were also analyzed. Methylation of LINE1 in WBC DNA is statistically significantly correlated with that in plasma DNA (R=0.32, p=0.04). WBC DNA global hypomethylation was significantly decreased in subjects with hepatitis C (HCV) infection (p=0.05). Plasma folate levels were not correlated with plasma DNA LINE1 methylation (R=0.13, p=0.41) or with WBC LINE1 methylation (R=−0.19, p=0.24). However, WBC folate levels were statistically significantly associated with patients’ survival. HCC patients who survived at least 3 months after diagnosis had lower WBC folate compared to patients who died within 3 months (p=0.004). We are currently expanding the HCC cohort and also analyzing biomarkers of chemical exposure (polycyclic aromatic hydrocarbons and aflatoxin B1) to investigate associations with methylation changes.

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 295. doi:10.1158/1538-7445.AM2011-295
Abstract 2951: Regulation of E2F-dependent transcription by the mTORC1 pathway
Authors: Law Brian K. , Corsino Pat E. , Law Mary E. , Jahn Stephan , Davis Bradley
Published: June 2012

mTORC1 inhibitors such as rapamycin and its analogs (rapalogs) are promising anticancer agents, which are effective against some tumors, yet ineffective against others. Understanding the mechanisms controlling tumor responsiveness or resistance to rapalogs is therefore critical. Much of the anticancer activity of mTORC1 inhibitors stems from inhibition of cancer cell proliferation and suppression of the endothelial cell proliferation required for angiogenesis. Rapalogs induce a G1 cell cycle arrest, which has been attributed to suppression of the translation of proliferation-associated proteins. However the exact mechanism by which mTORC1 inhibition results in G1 cell cycle arrest is unclear.

Since activation of E2F-dependent transcription is required for the G1/S-phase cell cycle transition, we examined the mechanisms by which rapamycin inhibits the expression of E2F1, which is itself encoded by an E2F-dependent gene. Rapamycin treatment decreased the binding of Cdk2 to the E2F sites of the E2F1 promoter in DNA oligonucleotide affinity purification experiments. This observation was corroborated by a decrease in Cdk2 binding to E2F4, p130, and p107, and a corresponding increase in Cdk2 binding to p27 in coimmunoprecipitation experiments. This suggests a model in which Cdk2 is recruited to E2F sites of promoters by complex formation with E2F4, p130, and p107 and functions to relieve the repression of these elements by maintaining p130 and p107 in their hyperphosphorylated forms. Consistent with this model, rapamycin treatment decreased kinase activity associated with E2F-DNA binding elements, but had little effect on overall Cdk2 activity in crude cell lysates. Rapamycin caused disruption of Cdk2/p130-, p107-, E2F4-containing complexes on E2F promoter elements. These results provide insights into how rapamycin treatment inhibits E2F-dependent transcription. It is hoped that further analysis of Cdk2/p130/E2F complexes will reveal mechanisms of tumor resistance to rapalogs and opportunities for optimizing the efficacy of mTORC1 inhibitors using combination 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 2951. doi:10.1158/1538-7445.AM2011-2951