bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 86: Inhibition of oncogenic Pim kinases, including Pim-2, alters cell growth and signaling in pancreatic cancer
Authors: Austin Dana M. , Nandiwada Vijaya B. , Baldino Carmen M. , Caserta Justin , Lee Chee S. , Flanders Yvonne , Dumas Stephane , Baines Antonio T. 
Published: August 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer of the pancreas, comprising over 85% of all cases. PDAC has a relative 1-year survival rate of 20% and a 5-year survival rate of 4%. A better understanding of the molecular mechanisms leading to the development of pancreatic cancer remains a major goal for defining appropriate treatment strategies and earlier detection. Past studies have shown that members of the oncogenic Pim kinase family (Pim-1, Pim-2, and Pim-3) are aberrantly expressed in a variety of solid tumors, including pancreatic cancer. Currently, only Pim-1 and Pim-3 have been shown to be anti-apoptotic and aberrantly expressed in PDAC. Although members of the Pim kinase family have been shown to have a high degree of homology at the amino acid level, past studies have demonstrated functional differences among the members of the Pim family. To better understand the significance of these observations, we have investigated the role of Pims, including Pim-2, in growth transformation of pancreatic cancer. We hypothesize that inhibition of Pim-2 will be effective in antagonizing the aberrant growth of PDAC. Initially, we confirmed by western blot analysis that Pim-2 is aberrantly expressed in PDAC tissues and cell lines. Also, we found that inhibition of Pim-2 expression by shRNA resulted in decreased cell viability of PDAC cells. Additionally, inhibition of PIm-2 expression resulted in decreased anchorage-independent growth. These effects were further demonstrated by inhibiting Pim activity using novel small molecule Pim inhibitors developed by Jasco Pharmaceuticals that inhibit Pim-2 activity in the picomolar range. To begin to determine a mechanism for this growth inhibition, we studied the activity of various downstream substrates of Pim kinases in PDAC cells such as 4EBP-1. Overall our research continues to validate the role of Pim-2 in growth transformation, as well as further support Pim-2 as a viable target for drug therapy in pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 86. doi:1538-7445.AM2012-86
Abstract 861: Selective small-molecule kinase inhibitors of the c-Src:FAK complex
Authors: Moroco Jamie A. , Gray Nathanael S. , Smithgall Thomas E. 
Published: August 2012

Abstract
The c-Src protein-tyrosine kinase is the prototype of a large non-receptor kinase family involved in a variety of signaling pathways in virtually every cell type. In normal cells, c-Src controls cell-cell adhesion, cell-matrix adhesion, and cell motility by interacting with and phosphorylating focal adhesion and extracellular matrix (ECM) proteins. Focal adhesion kinase (FAK), a key component of focal adhesions, activates c-Src by binding to its SH2 and SH3 domains and disrupting their negative regulatory influence on the kinase domain. The c-Src:FAK complex plays a major role in the migration and invasion of both normal and cancer cells. Both c-Src and FAK are over-expressed and constitutively active in many tumor types, enhancing focal adhesion turnover, cell migration and metastatic potential. The goal of our project is to determine whether distinct conformational changes occur in the c-Src kinase domain as a function of binding to FAK that can be selectively targeted with small molecule inhibitors. Using the FRET-based Z’-Lyte in vitro kinase assay, we first identified assay conditions where recombinant, downregulated c-Src activation was dependent on a synthetic phosphopeptide based on the FAK SH3- and SH2-binding motifs for c-Src. We then screened a chemical library of about 600 kinase-biased inhibitors for compounds that preferentially inhibited FAK-peptide-dependent c-Src activation compared to c-Src alone. Remarkably, 13 compounds showed at least five-fold selectivity for the FAK peptide:Src complex in the primary screen. Several of these compounds are of the Type II kinase inhibitor class and may exploit unique conformations of c-Src that are induced by FAK peptide binding to the SH3 and SH2 region of c-Src. These compounds are currently being evaluated for their impact on cell growth, invasion and migration in both fibroblasts and epithelial tumor cell lines. Discovery and development of selective inhibitors for a unique FAK-induced c-Src conformation may provide a new approach to targeted therapy for metastatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 861. doi:1538-7445.AM2012-861
Abstract 868: Oral SHP-1 inhibitor TPI-1a4 increases TILs in melanoma tumors and interacts positively with CTLA4 antibody for melanoma cure in mice
Authors: Yi Taolin , Lindner Daniel , Tuthill Ralph , Loibner Hans , Borden Ernest 
Published: August 2012

Abstract
SHP-1 phosphatase is a promising target for developing inhibitors as novel cancer immune therapeutics given its key role in negative regulation of immune cells. TPI-1a4 is a small molecule SHP-1 inhibitor identified recently and demonstrated activity for melanoma and colon cancer tumors in mice as a tolerated single oral agent. TPI-1a4 has been further evaluated herein for mechanism of action and potential clinical translation. Oral TPI-1a4 increased (up to 8x) in TILs in K1735 melanoma tumors in syngeneic mice in a dose-dependent manner and in correlation with tumor growth inhibition. The growth of 4-day established K1735 tumors (s.c.) in syngeneic C3H/HeJ mice was inhibited 44% (p &lt; 0.05) by TPI-1a4 at 0.4 mg/kg (5 d/wk, gavage) or 90% (p &lt; 0.01) at 0.8 mg/kg (5 d/wk, gavage) during a treatment period of 4 wks. Evaluation of tumor histology (H.E.) revealed increases (2x and 4x for the two treatments) of tumor-infiltrating lymphocytes (TIL). Immunohistochemistry analyses of the tumor samples demonstrate increases (∼3 and 6x) of CD45+ cells (pan-leukocytes), CD3+ cells (T lineage), B220+ cells (B/NK lineages), and Mac3+ cells (myeloid lineages). Oral TPI-1a4 interacted positively with CTLA4 antibody for survival extension and cure in K1735 melanoma tumor mice. TPI-1a4 (1 mg/kg, 5d/wk, gavage) or CTLA4 antibody (9H10, 100 ug x3, ip) as individual agents delayed tumor growth for ∼1-4 wks in C3H/HeJ mice with 4-day established K1735 tumors (s.c.). Their combination delayed tumor growth for 4-14 wks (4/5 mice) or completely blocked tumor growth (1/5 mice) by 20th wk in association with resistance to re-challenging with the melanoma tumor (s.c.). The combination was more effective in C3H/HeJ mice with 1-day established K1735 tumors, blocked tumor growth in most mice (4/5) comparing to mostly delayed tumor growth for several wks by the individual agents. TPI-1a4 in drinking water ad lib with weekly renewal was effective against the melanoma tumors in mice, suggesting chemical stability. Indeed, mass spectrometry verified structural integrity of TPI-1a4 stored as solid compound or in solvent at room temperature for 2 months. These data provide further evidences designate TPI-1a4 as a novel anti-cancer immune agent and a promising candidate for clinical translation. Our studies demonstrate for the first time the potential of TPI-1a4 to improve the clinical efficacy of CTLA4 antibody and other related cancer therapeutics. Future studies of TPI-1a4 analogs and derivatives are warranted and may lead to more refined and effective SHP-1 inhibitors and immune cell activators.
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 868. doi:1538-7445.AM2012-868
Abstract 869: Potent in vitro and in vivo anti-tumor activity of PI3K inhibitor BAY 80-6946 and MEK inhibitor BAY 86-9766 in preclinical biliary tract cancer models
Authors: Haegebarth Andrea , Haike Katja , Haike Katja , Paul Juliane , Mumberg Dominik , Ziegelbauer Karl , Liu Ningshu 
Published: August 2012

Abstract
Biliary tract cancer (BTC) includes a spectrum of genetically diverse invasive adenocarcinomas consisting intra- and extrahepatic cholangiocarcinoma (CC), and carcinoma arising from the gall bladder (GBC). Only 10% of patients diagnosed with early-stage disease are considered candidates for surgical resection, which offers the only chance for cure. The prognosis is poor for the majority of patients with locally advanced or metastatic BTC with a median survival of under a year. Recently, high incidence of oncogenic mutations such as KRAS, BRAF, PIK3CA and EGFR were found in BTC patients, potentially rendering these patients sensitive to inhibitors of these pathways. We report on preclinical evaluation of highly potent and selective PI3K inhibitor BAY 80-6946 and allosteric MEK inhibitor BAY 86-9766 in BTC as single agent and in combination. In vitro profiling a panel of BTC tumor cell lines indicated that KRASmut and PIK3CAmut cell lines were sensitive to MEKi (BAY 86-9766) and PI3Ki (BAY 80-6946), respectively, compared to the cell lines with wild type KRAS and PIK3CA. However, although MEKi BAY 86-9766 inhibited proliferation with IC50s of 147 nM in HuCCT-1 (KRASG12D) and 137 nM in EGI-1 (KRASG12D) cell lines, it can neither reach IC90 nor induce tumor apoptosis at concentration up to10 µM, indicating activation of additional survival pathways in these KRASmut BTC cell lines. When combining MEKi BAY 86-9766 with PI3Ki BAY 80-6946 in KRASmut EGI-1, IC90 could be reached at much lower concentrations, e.g. 108 nM of MEKi with 81 nM of PI3Ki in EGI-1 cells. Furthermore, strong activation (10-fold) of caspase3/7 was observed when EGI-1 cells were treated with 700 nM of MEKi with 230 nM of PI3Ki. To confirm the observed in vitro synergies, anti-tumor efficacy of BAY 80-6946 and BAY 86-9766 in mono- as well as combination therapy was evaluated in a set of human BTC xenograft models. Similar to the in vitro results, robust in vivo antitumor activities were observed in the PI3Ki and MEKi combination groups compared to monotherapy arms. Further detailed molecular mechanism on the synergistic inhibition of BTC tumor growth by combination of PI3K and MEK inhibitors, as well as in vitro and in vivo comparison to the chemotherapeutics will be presented. In conclusion, PI3Ki and MEKi combination therapy might open a new treatment paradigm for BTC to be developed in clinic.
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 869. doi:1538-7445.AM2012-869
Abstract 872: Identification of romidepsin (FK228) and its analogs as HDAC/PI3K dual inhibitors
Authors: Saijo Ken , Katoh Tadashi , Shimodaira Hideki , Oda Akifumi , Takahashi Ohgi , Ishioka Chikashi 
Published: August 2012

Abstract
Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. Therefore, inhibitors targeting PI3K are considered to be candidate drugs for cancer therapy. Indeed, some PI3K inhibitors have entered clinical trials, but efforts are still underway to develop new PI3K inhibitors. To discover novel PI3K inhibitors, we took advantage of a drug screening system by using the yeast Saccharomyces cerevisiae with deleterious mutations in ATP-binding cassette transporter genes. This is because wild-type yeast employs drug efflux pumps for reducing intracellular drug concentrations. The screening system is based on growth inhibition induced by overexpression of membrane localized p110α in yeast, in which no endogenous p110 homolog is expressed. However, compounds with the ability to inhibit PI3K can rescue cells from p110α induced growth inhibition. Using this system, we screened the deposited chemical library of the Screening Committee of Anticancer Drugs (SCADS). As a result, the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs were isolated. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at μM-range concentrations. FK-A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of v-akt murine thymoma viral oncogene homolog (AKT) and downstream signaling components. Molecular modeling of the PI3K-FK228 complex indicated that FK228 binds to the ATP binding pocket of p110α. At µM range concentrations, FK228 and FK-A5 exhibit potent cytotoxicity even in HDAC inhibitor-resistant cells. Fluorescence activated cell sorting (FACS) and western blotting indicated apoptosis as the cause of cell death. Furthermore, it was suggested that HDAC/PI3K dual inhibitory activity of FK228 and FK-A5 at µM range concentrations contributed to the induction of potent apoptosis because of the following reasons. 1) FK228 or FK-A5 within µM range inhibited AKT phophorylation and acetylated histones simultaneously. 2) The apoptosis induction by FK228 or FK-A5 at µM range concentrations was mimicked by combination of HDAC inhibitor and PI3K inhibitor. In conclusion, we demonstrated that FK228 and its analogs directly inhibited PI3K activity and induce potent apoptosis exhibiting HDAC/PI3K dual inhibition at µM range concentrations. In future, optimizing potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment.
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 872. doi:1538-7445.AM2012-872
Abstract 88: Stabilizing but not activating β-catenin by E-cad/CTF2
Authors: Hsu Sheng-Chieh 
Published: August 2012

Abstract
E-cadherin is an important mediator of cell-cell adhesion and plays a vital role to modulate intracellular signaling pathways. E-cadherin binds p120catenin (p120) and β-catenin at cadherin homology 2 (CH2) domain and CH3 domain, respectively. Recent studies show E-cadherin could be cleaved by γ-secretase and released the intracellular C-terminal fragment 2 (E-cad/CTF2) to regulate the p120-kaiso mediated signaling pathway in the nucleus. However, the functional effect of E-cad/CTF2 on its binding partners, β-catenin and p120, remains elusive. Here, we show E-cad/CTF2, like full-length E-cadherin, can interact and increase the expression of β-catenin. Using reverse transcription-quantitative PCR (RT-qPCR), the transcription of β-catenin mRNA is not affected by the expression of E-cad/CTF2 or E-cadherin. Interestingly, while the nuclear expression of β-catenin is enhanced by E-cad/CTF2 or NLS-tagged E-cad/CTF2, the transcriptional activity of β-catenin does not increase. It indicates the interaction between E-cad/CTF2 and β-catenin is much stronger then TCF4/β-catenin complex. This study provides the evidence that the transcriptional activity of β-catenin is not activated by E-cad/CTF2 although the stability of β-catenin is greatly enhanced by E-cad/CTF2.
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 88. doi:1538-7445.AM2012-88
Abstract 884: Basonuclin1 (BNC1): A novel therapeutic target in ovarian cancer identified through integrative TCGA-based functional genomic analysis
Authors: Wu Sherry Y. , Unruh Anna K. , Bartholomeusz Geoffrey , Ivan Cristina , Pecot Chad V. , Rupaimoole Rajesha , Han Hee-Dong , Bottsford-Miller Justin , Tucker Susan L. , Coleman Robert L. , Lopez-Berestein Gabriel , Baggerly Keith A. , Sood Anil K. 
Published: August 2012

Abstract
High-grade serous ovarian cancer (HGS-OvCa) is the most common and lethal type of ovarian carcinoma. While TCGA provides comprehensive genomic profiling of clinically annotated HGS-OvCa tumors, identification of novel therapeutic targets using this dataset is still needed. We coupled TCGA mRNA expression and clinical response data to systematically identify genes which could alter progression of HGS-OvCa and investigated associated alterations in DNA promoter methylation and microRNA expression. For selected targets, we also used siRNA functional studies to clarify gene-specific effects. We identified 102 genes as up-regulated in tumors from patients whose cancer had progressed within 7 months of diagnosis (chemo-resistant group: 53 cases) compared to tumors from patients who had no disease progression for more than 3 years (chemo-sensitive group: 57 cases). These genes had two-sample t-test p-values &lt; 0.05 according to level 3 TCGA data from both Agilent and Affymetrix platforms. Basonuclin1 (BNC1), a transcription factor which regulates ribosomal biogenesis, cell proliferation, and epithelial differentiation, was one of the key targets identified. Its expression was found to be increased by more than two-fold (Agilent platform; p=0.001) in chemo-resistant tumors. While no significant associated changes in microRNA expression were evident in TCGA for the BNC1 gene, we found that the expression of BNC1 negatively correlated with the degree of methylation at the promoter region of transmembrane 4 superfamily member 1, TM4SF1 (-0.42, Agilent platform), a known up-regulated pro-angiogenic gene in ovarian cancer. Importantly, the siRNA functional study had revealed a 35% reduction in cell viability in cisplatin-resistant A2780-CP20 cells following BNC1 siRNA treatment, and a further 15% reduction was noted when the cells were treated with cisplatin at the IC30 concentration determined using the chemo-sensitive parental cell line. Overall, our results demonstrate (a) the feasibility of using TCGA data, coupled with functional siRNA studies, to identify novel targets for the treatment of ovarian cancer and (b) the potential of targeting BNC1 as a treatment strategy.
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 884. doi:1538-7445.AM2012-884
Abstract 885: Integrated analysis of colorectal cancer cell lines reveals an amplicon driver which may be involved in platinium resistance
Authors: Briffa Romina , Harrison David J. , Faratian Dana 
Published: August 2012

Abstract
Background: First line adjuvant treatment for colorectal cancer (CRC) is 5-fluorouracil and the platinum compound oxaliplatin. New targeted therapies such as cetuximab and PI3K/mTOR inhibitors are being developed in order to improve therapeutic outcomes. However, intrinsic and acquired resistance is common and selecting patients who are likely to respond remains a clinical and pathological challenge. The aim of this study is to identify new targets for therapy using an integrated genomic, transcriptomic, proteomic, and functional analysis of CRC cell lines. Methods: Cell proliferation assays (AlamarBlue) were carried out on a panel 15 colorectal cancer cell lines. IC50s were established for 5-fluoruracil, oxaliplatin, and BEZ-235, a PI3K/mTOR inhibitor. Cell lines were profiled using reverse phase protein arrays (RPPA) for protein expression, Illumina gene expression analysis, array comparative genomic hybridization (aCGH; NimbleGen 135k chips) and targeted sequencing of hotspot mutations. Associations of mutations, transcript, copy number variations and proteome with drug sensitivity were established using correlation coefficients and integrated network analysis. Validation of copy number gains and losses was performed in primary tumors using Oncomine to interrogate public databases. Results: IC50s varied from resistant to highly sensitive for all three compounds. BRAF V600E mutation was significantly associated with response to 5 fluorouracil (p = 0.006). There were 17 regions of recurrent amplification across 14 cell lines and 48 regions of loss. The frequently and highly amplified regions included 8q24.13 - 8q24.21 which was significantly correlated with oxaliplatin response (p = 0.031), and amplified in 11% of primary CRCs on interrogation of public databases. This amplified region contains the putative oncogene TRIB1, a cell signaling regulator, which was correlated with gene expression across the cell lines and was found to be significantly correlated to the AKT (p=0.026), phosphor-mTOR (Ser2481) (p = 0.017) and phosphoSRC (Thr24) (p = 0.020) protein expression. The recurrently deleted regions included 3p14.2 which was significantly associated with response to the PI3K/mTOR inhibitor BEZ235 (p=0.031). This region was found to be significantly correlated with MEK (p=0.042) and phosphoCDK2 (Thr160) (p=0.018) protein expression, and contained the putative tumor suppressor gene FHIT, a hydrolase involved with purine metabolism. Conclusions: TRIB1 is a potential oncogenic driver in CRC which may be associated with therapeutic resistance to platinum compounds.
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 885. doi:1538-7445.AM2012-885
Abstract 889: Integration of centrosome-associated and kinase-related screens to identify centrosome amplification-related synthetic lethal interactions
Authors: Drosopoulos Konstantinos , Scott Carly , Tang Chan , Linardopoulos Spiros 
Published: August 2012

Abstract
Centrosome amplification is one of the most commonly observed abnormalities in human cancer and is associated with increased chromosome instability (CIN), aneuploidy and tumor progression. Cancer cells have been shown to cluster supernumerary centrosomes in a bipolar fashion in mitosis, thus preventing the formation of lethal multipolar spindles. We have developed isogenic cell lines, which enable us to identify genes which selectively kill tumor cells with centrosome amplification. The model is based on the generation of genomically stable human colon cancer DLD1 diploid and tetraploid (DLD1-T) cells with normal centrosome numbers and genomically unstable DLD1 intermediate (DLD1-I) with extra centrosomes generated by transiently blocking cytokinesis. Diploid and tetraploid populations did not show significant differences in gene expression, fitness, rate of spontaneous apoptosis, centrosome amplification and mitotic abnormalities. However, growth rate examination of the generated isogenic cell lines showed a slight increase in doubling time of DLD1-I clones, possibly due to a longer activation of the mitotic checkpoint machinery to allow time for microtubule attachment and centrosome clustering. To identify genes that their ablation leads to a selective cell killing of centrosome amplified cancer cells by centrosome declustering, we envisaged two parallel paths of investigation, an siRNA and a chemical library screening with a two-fold readout assay: a cell viability and a spindle morphology phenotypic assay by high-content microscopy. This approach allowed us to identify target genes and generate networks of genes that specifically kill cells with centrosome amplification by preventing centrosome clustering.
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 889. doi:1538-7445.AM2012-889