bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3851: Killing of Kras mutant colon cancer cells by the αGBP cytokine, a physiological PI3K inhibitor therapeutically effective in vivo
Authors: Mallucci Livio , Lotti Lavinia V. , Mariani-Costantini Renato , Wells Valerie , Zicha Daniel 
Published: August 2012

Abstract
Activating Kras mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream pathways responsible for cell proliferation and cell survival have been shown to be deregulated by oncogenic Kras but there are no effective targeted therapies to date for Kras driven oncogenesis. Mutant-activated Kras defines a subset of patients for whom prognosis is poor and therapeutic options are limited. We demonstrate that αGBP, a cytokine produced by CD4+ and CD8+ activated T cells, which operates by inhibiting class IA and class IB PI3K, is a potent activator of apoptosis in Kras-mutant colorectal cancer cells, even when co-harboring mutant-activated PIK3CA. Mechanics initiate with inhibition of PI3K activity and Rac-independent actin reorganisation assignable to phosphoinositide changes at the plasma membrane. Cyclin E deregulation, arrest of DNA synthesis and Chk2 activation underscore events critical to the activation of intrinsic apoptosis. Clustering of CD95/Fas death receptors underscores events critical to the activation of extrinsic apoptosis. In nude mice we present the first evidence that tumor development is strongly inhibited. This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-αGBP may be therapeutically effective against other cancers harbouring activating Ras mutations. Wells, V. and Mallucci, L. (2009). Phosphoinositide 3-kinase targeting by the β-galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death. Breast Cancer Research 11, R2, 1-10. Wells, V., Downward, D. and Mallucci, L. (2007). Functional inhibition of PI3K by the αGBP molecule suppresses Ras-MAPK signalling to block cell proliferation. Oncogene 26, 7709-7714. Mallucci, L. and Wells, V. (2007). Alternative use of signaling by the αGBP cytokine in cell growth modulation and cancer control. From surveillance to therapy. In: Apoptosis, Cell Signaling and Human Diseases. Ed. R. Srivastava. The Humana Press Inc. Vol. I, 203-216. Patents US patent no. 7,994,113 granted August 9th 2011 PCT WO 2008/152392: Europe, Canada, Australia, Japan, published
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3851. doi:1538-7445.AM2012-3851
Abstract 3855: Inhibitors of apoptosis (IAPs) in gastrointestinal stromal tumors
Authors: Falkenhorst Johanna , Mühlenberg Thomas , Simon Susanne , Ecken Sonja , Henze Joern , Grabellus Florian , Breitenbücher Frank , Schuler Martin , Fletcher Jonathan A. , Bauer Sebastian 
Published: August 2012

Abstract
Introduction Gastrointestinal stromal tumors (GIST) are characterized by gain-of-function-mutations of c-KIT or PDGFRA. Despite long-lasting remissions with the KIT inhibitor imatinib (IM) most patients eventually progress. While inhibitors of apoptosis proteins (IAPs) may confer resistance in other cancers little is known about the role of IAPs in GIST. Material and Methods IAP expression (cIAPs, XIAP, survivin) in patient samples (TMA, n=163), IM-sensitive (GIST-T1, GIST882, GIST430) and IM-resistant (GIST48B, GIST48) GIST cell lines (RT-PCR, western blot) was analyzed. The impact of KIT and growth inhibitory drugs on IAP expression (24h of treatment) was determined by western blot. Biological consequences of IAP modulation (YM155: transcriptional repressor of survivin; Embelin: biochemical XIAP inhibitor; lentiviral shRNA knockdown [KD] of survivin, XIAP) were investigated alone and in combination with KIT-related pathway inhibitors (IM, LY294002, 17-AAG). Results cIAPs, XIAP and survivin were expressed at various levels in all KIT-positive and negative GIST cell lines. Resistant cell lines did not exhibit higher levels of IAPs. Survivin expression was found to vary over time in GIST-T1 and 48B (2- and 4-fold within 5 days. Survivin expression (immunoreactivity score α3) was found in 40% of GIST patients. PI3K inhibition led to survivin downregulation of 20 to 65% (24h) in all tested cell lines whereas KIT inhibition (IM, 24h) reduced survivin and XIAP expression only in GIST-T1 (52%). The protein levels of both XIAP and survivin were decreased following HDAC (SAHA: 44-71%, except GIST430) and MDM2 inhibition (survivin: 40 - 90%). YM155 downregulated survivin and exhibited proapoptotic and antiproliferative effects in all cell lines at low nM levels (IC50: GIST-T1: 4nM, GIST48P: 40nM, GIST48B, GIST 882: 80nM) except GIST430 (IC50&gt;1µM). No antagonistic effects were seen with combinational treatment. Embelin treatment resulted in IC50 levels of 40µM - 300µM while lacking a specific XIAP inhibition. A stable XIAP KD was established in GIST-T1 resulting in slower growth (25% in 3d). Conclusion IAPs are commonly expressed in GIST cell lines regardless of resistance to IM. Expression levels are mostly independent from KIT inhibition but proapoptotic effects from HDAC and MDM2 inhibitors may in part be conferred by IAPs. The survivin repressor YM155 showed antiproliferative and proapoptotic effects at levels that are therapeutically achievable suggesting a potential therapeutic role in GIST.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3855. doi:1538-7445.AM2012-3855
Abstract 3858: Gains in FGF19 are predictive of response to the fibroblast growth factor receptor (FGFR) small molecule tyrosine kinase inhibitor BGJ 398 in vitro
Authors: Finn Richard S. , Aleshin Alex , Zhao Danyun , Anderson Lee , Ginther Charles , Dering Judy , Shi Michael , Porta Diana Graus , Busuttil Roanld W. , Slamon Dennis J. 
Published: August 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer death world-wide. Sorafenib, a multi-targeted small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor and other kinases is the only approved systemic agent in advanced HCC. Despite multiple studies defining the molecular heterogeneity of HCC, clinical trials of new agents do not pre-select for predictive markers. The fibroblast growth factor (FGF) receptor consists of 4 receptor tyrosine kinases and over 20 ligands. Differential expression and activation of these receptors and ligands have been implicated in oncogenesis and the pathogenesis of HCC (Sawey 2011). BGJ398 is a selective small molecule tyrosine kinase inhibitor of the FGFR family of receptors 1-4. Given the molecular diversity of HCC, we hypothesized that there would be a subset of HCC that would be more dependent on FGFR inhibition and used cell line models to identify predictive markers of response to BGK 398. Methods: 20 human HCC cell lines were used. In vitro dose response curves were generated using direct cell count assays over 6 days. IC 50 values were calculated from the dose response curves. Genomic data on the cell lines was derived using the Agilent 105K CGH platform. These data were analyzed in the context of the sensitivity data to BGJ 398. Western blot analysis was performed for effects of BGJ398 on phospho-FRS2Δ (tyr-196), a downstream signaling molecule for FGFR activation. Flow cytometry was performed for effects of BGJ 398 on the cell cycle and apoptosis. Results: There was differential sensitivity to BGJ 398 across the HCC cell lines. 3 cell lines were identified as having IC 50 values less than 1 μM versus the remaining cell lines which were all &gt;1 uM. When analyzed in the context of the CGH data, all 3 cell lines had gains in FGF 19 of log2 ratio of 0.9 to 2.6. BGJ inhibited FRS2α activation in all cell lines tested. Flow cytometry revealed the BGJ induced cell cycle arrest in sensitive lines without significant apoptosis. Conclusions: Gains in FGF19 are predictive for growth inhibitory effects of BGJ398 in human HCC cell lines in vitro and provide rationale for patient selection in clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3858. doi:1538-7445.AM2012-3858
Abstract 3889: Substituted pyrrolo[2,3-d]pyrimidines as water soluble microtubule targeting agents
Authors: Gangjee Aleem , Lin Lu , Mooberry Susan L. , Hamel Ernest 
Published: August 2012

Abstract
Microtubules play critical roles in cell functions, and microtubule targeting agents have been successfully developed as anti-cancer drugs. Based on the binding sites, microtubule targeting agents are divided into three broad classes: vinca alkaloid, taxane and colchicine site binders. Vinca alkaloids and taxanes, represented by vinorelbine and paclitaxel, respectively, have been widely used in cancer chemotherapy. However, drug resistance associated with over-expression of Pgp or αIII-tubulin has greatly reduced the therapeutic value of these drugs (e.g., paclitaxel is over 800-fold less active against Pgp over-expressing cancer cells). Another persistent issue with vinca alkaloids and taxanes is their poor water solubility. Administration of paclitaxel needs to be performed by trained personnel with special reagents and equipment. Colchicine site binders, such as colchicine or combretastatin A-4 (CA4), have not received clinical approval for wide use in the treatment of cancer. Novel water soluble colchicine site binding agents are potentially valuable alternatives for use alone or in combination with existing microtubule targeting drugs, especially in overcoming drug resistance. We previously reported a series of substituted pyrrolo[2,3-d]pyrimidine compounds as water soluble, colchicine site binding agents. One of the highly active compounds has shown sub-micromolar to nanomolar inhibitory activities against the NCI-60 panel cell lines. The same compound exhibits enhanced or equal inhibition against Pgp and αIII-tubulin over-expressing cell lines. In a continuing effort to find new agents with these properties, 2,4-disubstituted pyrrolo[2,3-d]pyrimidine analogs AG114 - AG119 and AG477A were designed and synthesized. Among the analogs tested, AG477A showed an IC50 of 10 ± 0.7 μM in inhibiting tubulin assembly. In drug resistance assays, AG477A showed sub-micromolar inhibitory activity (IC50) against the Pgp over-expressing cell line NCI/ADR-RES (0.89 ± 0.3 μM), as compared with the parental OVCAR-8 cell line (1.2 μM). In addition, AG477A is readily converted to a highly water soluble hydrochloride salt, which marks a significant advantage over existing microtubule targeting agents in clinical use. Structure activity studies show a requirement for the 4-position N-methyl-4-methoxyaniline moiety for antitubulin effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3889. doi:1538-7445.AM2012-3889
Abstract 3900: Discovery of FQIT: An imidazo[5,1-f][1,2,4]triazine derived dual IGF-1R/IR inhibitor
Authors: Jin Meizhong , Gokhale Prafulla , Cooke Andy , Foreman Kenneth , Buck Elizabeth , May Earl , Feng Lixing , Bittner Mark , Kadalbajoo Mridula , Landfair Darla , Siu Kam , Stolz Kathryn , Werner Douglas , Laufer Radoslaw , Li An-Hu , Dong Hanqing , Steinig Arno , Kleinberg Andrew , Yao Yan , Pachter Jonathan , Wild Robert , Mulvihill Mark 
Published: August 2012

Abstract
Insulin-like growth factor-1 receptor (IGF-1R) has been recognized as a major target in cancer drug discovery due to its strong implications in various stages of tumorigenesis based on accumulated preclinical data over the years. Recent research on compensatory crosstalk between IGF-1R and insulin receptor (IR) signaling pathways suggests that targeting both receptors is critical to fully blocking the IGF signaling axis. Therefore, inhibition of both receptors is anticipated to result in a more therapeutically beneficial response than targeting IGF-1R alone (e.g. IGF-1R specific antibodies). These findings provided the biological rationale as well as set the foundation for the pursuit and ultimate discovery of OSI-906 (linsitinib), a small molecule dual IGF-1R/IR inhibitor currently in clinical development. As part of OSI's ongoing investment in a small molecule drug discovery platform targeting IGF-1R and IR, a new series of potent and selective imidazo[5,1-f][1,2,4]triazine derived inhibitors of IGF-1R and IR have been identified. Structure-activity relationships and optimization driven by structure-based drug design (SBDD) leading to the discovery of FQIT, a potent, highly selective, well-tolerated and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in multiple tumor xenograft models will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3900. doi:1538-7445.AM2012-3900
Abstract 3901: Estrogen receptor conformation sensing small molecules as novel anti-cancer agents
Authors: Rankin Bethany , Rajnarayanan Rajendram V. , Koyack Marc 
Published: August 2012

Abstract
Estrogen mediated signaling affects cell proliferation, differentiation and mammary gland function. The human Estrogen Receptor (hER) is present in 70% of breast cancers. Consequently, estrogen mediated hER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment.Anti-estrogen, Tamoxifen, targets the LBD and transitions the hER from “agonist” conformation into a structurally unique “antagonist” conformation, which is distinctly recognizable by the position of helix XII. Antiestrogen tamoxifen is a known treatment for hER positive breast cancers. However, due to mutations and hormone-independent activation of/in the hER, breast cancers develop resistance to tamoxifen, and resume growth and malignant progression. Estrogen's action at hER is regulated not only by estrogen, but also by other small molecules and coregulators. A closer look at the compliment of coregulators during acquired tamoxifen resistance shows a significant decrease in the corepressor breast cancer susceptibility (BRCA1) protein expression. BRCA1 directly interacts, from amino acids 67-200, with the hER, from 338-379 and 420-495, LBD/AF2 domain. The interface region of BRCA1 containing the binding motif (amino acids 86-93), which specifically contain two essential chemical features, a hydrophobic core and a charged carboxylic acid is necessary for high affinity binding and hER repression. Here we present several small molecules identified based on these pharmacophoric features as well as ER molecular profiles of conformation sensing peptides. Discovery of conformation sensing protein/peptides would open new avenues for drug development and would lead to advanced clinical studies of hER-conformation sensing small molecules as an entirely new class of anticancer therapy especially in tamoxifen-resistant tumors. Acknowledgements: This research was supported via funds from the New York State, National Institutes of Health (5P20MD002725), through the NCMHD -RIMI program (RVR) and NSF LSAMP Bridge to Doctorate grant (BR).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3901. doi:1538-7445.AM2012-3901
Abstract 3912: The discovery of AZD4547: An orally bioavailable, potent and selective N-(5-Pyrazolyl)benzamide FGFR1-3 inhibitor
Authors: Thomas Andrew P. , Theoclitou Maria-Elena , Buttar David , Ruston Linette , Wrigley Gail , Dennis Mike , Rudge David A. , Coleman Tanya , Smith Robin , Gavine Paul R. , Klinowska Teresa , Mooney Lorraine , Brooks Nigel 
Published: August 2012

Abstract
There is increasing evidence that FGFR signaling plays an important role within human cancer, with members of FGFR family acting as driving oncogenes in a significant number of human tumors. Deregulation of FGFR-signaling has been documented within clinical samples of breast multiple myeloma, bladder, endometrial, gastric, squamous NSCLC and prostate cancers. This dysregulation most frequently occurs through gene amplification, or through genetically altered forms of FGFR proteins. This increasing body of evidence implicating FGFR signaling in cancer has provided rationale for the identification and testing of selective inhibitors of FGFR signaling in the clinic. In this presentation, we describe the progress of our FGFR tyrosine kinase inhibitor programme and report the discovery of N-(5-pyrazolyl)benzamide FGFR inhibitors. Early compounds in this series suffered from poor in vivo pharmacokinetic (PK) properties. The key site of metabolism was identified to be at a basic N-methyl group. This group was shown to be located in the solvent channel of the ATP binding site on binding to FGFR1, and modification could be made without causing major changes to intrinsic binding affinity. However, the first compounds identified with low metabolic clearance also showed a significant reduction in oral bioavailability, due to apparent low permeability and increased efflux potential. The characterization of these PK issues and the discovery of compounds which overcame them, through modulation of pKa, lipophilicity and masking of the polar groups, will be described. Leading compounds showed significant anti-tumor activity in xenograft tumors grown in mice. Detailed characterization of these compounds led to the identification of AZD4547, a potent and selective FGFR tyrosine kinase inhibitor currently in Phase I clinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3912. doi:1538-7445.AM2012-3912
Abstract 3914: Androgen receptor (AR) degradation is controlled by the co-operation of PMEPA1 and the E3 ubiquitin ligase NEDD4-1
Authors: Li Hua , Dobi Albert , Srivastava Shiv 
Published: August 2012

Abstract
Introduction and Objective: Androgen receptor (AR) plays critical roles in prostate growth and differentiation and prostate tumorigenesis. Our recent investigations have discovered a novel mechanism of AR degradation in CaP cells involving PMEPA1 and NEDD4-1 which is independent of MDM2. Previously we have shown that PMEPA1 is a highly androgen-inducible gene in CaP cells that recruits the NEDD4-1, an E3 ubiquitin ligase, to degrade AR. In an independent study NEDD4-1 has been identified as an E3 ligase controlling the levels of PTEN. We hypothesize that decreased or loss of PMPEA1 expression that is frequently observed in human prostate tumor cells may lead to enhanced AR functions. Elevated AR levels may increase NEDD4-1 and in turn destabilize PTEN in prostate cancer cells. Here, we further investigate the co-operation between PMEPA1 and NEDD4-1 to alter AR and PTEN protein levels. Methods: PMEPA1 and NEDD4-1 were ectopically expressed in androgen responsive LNCaP and VCaP cells by pCMV-XL4 and pcDNA3.1 vectors, respectively. AR, PMEPA1, NEDD4-1, MDM2 and PTEN were silenced by using specific siRNAs. Cell growth was monitored in response modulation of PMEPA1, NEDD4 and AR. Protein levels of AR, PMEPA1, NEDD4-1, PTEN and PSA were assessed by immunoblot assays. Results: Decreases in AR protein levels, inhibited AR signaling and cell growth in response to heterologous expression of NEDD4-1. Consistent with this observation, inhibition of NEDD4-1 by siRNA resulted in elevated AR protein levels, AR signaling and increased cell growth. Reduced cell growth by AR knock-down or by heterologous expression of NEDD4-, were rescued by the knockdown of PMEPA1. It was also shown that AR up-regulates the expression of NEDD4-1 in hormone responsive CaP cells. In VCaP cells, overexpression of NEDD4-1 resulted in decreased PTEN protein levels. Remarkably, PMEPA1 knockdown resulted in elevated AR and NEDD4-1 levels and the downregulation of PTEN protein. Conclusions: NEDD4-1 mediated AR degradation in hormone responsive CaP cells requires PMEPA1. The frequently observed decreased expression of PMEPA1 results in elevated AR protein levels and may facilitate NEDD4-1 mediated degradation of PTEN in CaP. Our findings revealed a complex interplay of the AR, PMEPA1, NEDD4 and PTEN underscoring the impact of the loss of PMEPA1 to increased AR and decreased PTEN, both proteins critical in prostate tumorigenesis. This study is supported by the NIH grant (R01CA106653) to SS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3914. doi:1538-7445.AM2012-3914
Abstract 3921: Androgens stimulate phosphorylation of ERK and AKT in thyroid cancer cells
Authors: MacEwan Melanie , Swati Ismatun , Xie Suqing , Ardacheva Olena , Iacob Codrin , Shin Edward , Moscatello Augustine , Schantz Stimson , Tiwari Raj K. , Geliebter Jan 
Published: August 2012

Abstract
Thyroid cancer is the most common endocrine malignancy with the papillary variety comprising ∼85% of thyroid neoplasms. While the greatest incidence of PTC is in women of childbearing age, the occurrence of PTC in men and postmenopausal women is associated with increased aggressiveness and poorer clinical outcomes. This gender disparity suggests that while the initiation of PTC is driven by estrogens, its progression may be mediated by androgens. Immunohistochemical analysis of PTC specimens from 5 male and 15 female patients indicated that all expressed androgen receptors (AR). AR mRNA was detected in equivalent amounts in three thyroid cell lines, but the PTC cell lines, BCPAP and TPC-1 expressed significantly more AR protein (4.6 fold and 3.9 fold, respectively) than the “normal” T-antigen transformed thyrocyte cell line, Nthy-ori-1. The treatment of the cell lines with the synthetic androgen, R1881 (10nM) resulted in increased phosphorylation of ERK and AKT in all three cell lines. Nthy expressed 2 fold more pERK when treated with R1881 whereas pAKT, which was previously undetected increased to significantly higher levels. R1881 addition increased pERK and pAKT 3 fold and 2 fold, respectively, in the male, RET/PTC cell line, TPC-1. pERK and pAKT were undetectable in the female, BRAFV600E cell line and were significantly induced by R1881.The known role of ERK and AKT in cellular proliferation, migration and invasion, and the activation of these molecules by androgens, may provide the mechanistic basis for the gender disparity in PTC aggressiveness and clinical outcome between young women and men/postmenopausal women.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3921. doi:1538-7445.AM2012-3921