bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2618: Identification of multidrug response genes by meta-analysis based on ChemoFx® in human breast cancer cell lines
Authors: Shen Kui , Rice Shara , Wang Dakun , Gingrich Dave , Brower Stacey , Ervin Paul , Gabrin Michael , Song Nan 
Published: February 2011

Abstract
The success of chemotherapeutic agents to treat various forms of cancer has a long history. Unfortunately, a major cause of treatment failure is drug resistance to currently available chemotherapy agents. Understanding the mechanism of resistance to multiple drugs has been a subject of considerable interest. ChemoFx® holds the promise of not only determining which patient will respond to what therapy but also can be used to learn more about drug resistance while acting as a proxy to clinical outcome.
In this study, we used the ChemoFx® to identify response vs. non-response to seven different chemotherapeutic agents (paclitaxel, docetaxel, epirubicin, doxorubicin, gemcitabine, fluorouracil, cyclophosphamide) in 28 human breast cancer cell lines. Based on publically available gene expression profiles of these breast cancer cell lines and the ChemoFx® results, differentially expressed (DE) genes related to multi-drug response were identified through meta-analysis method. Five hundred thirty six DE genes were identified to be related to multidrug response at the false discovery rate of 0.05. To segregate the effect of ER status, we also performed meta-analysis within ER positive or ER negative breast cancer cell lines separately. Thirty seven DE genes were identified related to multiple drug response in ER negative breast cancer cell lines and 20 DE genes in ER positive cell lines. Among all these DE genes, only one is in common between ER positive and ER negative groups. These results suggest that multi-drug resistance is the result of not just one gene but the contribution of multiple genes. In addition, gene set enrichment analysis showed that multidrug response genes are involved in different biological processes in ER positive vs. ER negative cell lines. The dissimilarity of multidrug response genes in ER positive vs. ER negative shows the value of integrating multidrug response gene information with clinical factors to identify patients who are unlikely to benefit from current chemotherapeutic drugs. Moreover, understanding the mechanisms of multidrug response has the potential of identifying new therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2618.
Abstract 2619: Sulfation of toremifene: Individual variability, isoform specificity, and contribution to toremifene pharmacogenomics
Authors: Edavana Vineetha Koroth , Williams Suzanne , Beggs Marjorie L. , Mercer Kelly , Yu Xinfeng , Zhang Xuemei , Caldwell David B. , Kadlubar Fred , Kadlubar Susan 
Published: February 2011

Abstract
Toremifene (TOR) is a selective estrogen receptor modulator (SERM) used in adjuvant therapy for breast cancer, and more recently is in clinical trials for prostate cancer prevention in patients with high grade PIN. The chemical structure of TOR differs from tamoxifen (TAM) only by the presence of a chlorine atom in the ethyl side chain. That difference results in distinct breakdown products of the two drugs, which may provide for a more favorable toxicity spectrum with TOR compared to TAM. TOR has a similar mechanism of action to that of TAM, in that its 4-hydroxy metabolites bind specifically to estrogen receptors and, as an estrogen receptor-TOR complex, to chromatin. Interestingly, studies have indicated that a subset of patients who fail on TAM therapy benefit from high-dose TOR therapy, indicating that pharmacogenomics could be an important determinant of response to treatment with TOR.
Several studies have indicated that functional genetic variants in the TAM metabolic pathway influence response to therapy, but to date, pharmacogenomic studies of patients treated with TOR are lacking. In order to perform candidate gene association studies, it is necessary to identify the enzymes involved in TOR metabolism. While the Phase I metabolism of TOR has been well-characterized, Phase II metabolism of the active 4-OH-TOR is not well-defined. In this study, we examined individual variability in sulfation of TOR, and found 20-fold variation in human liver cytosols from 100 subjects. Examination of recombinant sulfotransferases revealed that SULT1A1, SULT1E1, and to a lesser extent, SULT2A1 catalyzed the sulfation of TOR. SULT1A1 is the most highly expressed hepatic sulfotransferase, and there was a significant association between SULT1A1*1/*2 genotype and TOR sulfation in human liver cytosols (p=0.001). Since target tissue metabolism is also a critical determinant of clinical efficacy, we also examined the presence of sulfotransferase isoforms in normal prostate (n= 8), BPH tissue (n= 12), and prostate cancer (n=4). Quantitative RT-PCR analysis showed the presence of SULT1A1 and SULT2B1b in BPH and Prostate cancer tissues. These results indicate that variability in sulfation, in terms of both first-pass metabolism and target tissue metabolism, contributes to response to TOR for prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2619.
Abstract 2625: Proteasome inhibitor Bortezomib increases anti-cancer activity of novel anti-inflammatory anti-androgen Compound A
Authors: Yemelyanov Alexander , Budunova Irina 
Published: February 2011

Abstract
Signaling by the steroid hormone receptors plays a pivotal role in the development of prostate cancer. Androgens and the androgen receptor (AR) promote prostate tumorigenesis. In contrast, the glucocorticoid receptor (GR) plays tumor suppressive role in the prostate. The major molecular mechanisms underlying GR anti-cancer and anti-inflammatory effects are similar and based on GR transrepression that involves negative interaction between GR and other transcription factors. We anticipated that anti-inflammatory anti-androgens hold a great potential for prostate cancer treatment. Thus, we identified the potential AR/GR ligands with this functional profile by screening of selective GR activators (SEGRA) recently synthesized in USA and Europe as anti-inflammatory GR ligands with reduced side effects. The lead identified compound is Compound A (CpdA), a synthetic analogue of a hydroxyphenyl aziridine precursor isolated from the Namibian shrub Salsola Botschantzev. We and others showed that CpdA inhibits AR function, prevents GR dimerization and transactivation, but strongly enhances GR transrepression. It is known that proteasome inhibitors tightly control GR and AR degradation and function. We show here that the exposure of prostate cancer cells expressing endogenous AR and GR to proteasome inhibitor Bortezomib (BZ) resulted in strong degradation of AR and accumulation of GR. The androgen DHT prevented AR destabilization induced by BZ. In contrast to androgen, CpdA cooperated with BZ to decrease AR expression and function. In addition, BZ modified the functional profile of GR in a ligand-dependent fashion. In the presence of GR modulator CpdA, BZ did not induce GR transactivation but augmented CpdA effect on GR transrepression measured by the inhibition of several transcription factors such as NF-kB, AP-1 and STAT1. Finally we revealed a strong cooperation between CpdA and BZ in activation of apoptosis and endoplasmic reticular stress in prostate cancer cells. Overall, our data suggest that combination of BZ with steroid receptor modulators such as CpdA, has a high potential for PC therapy. Work is supported by RO1CA118890 (to IB) and ACS IL grant #160185 (to AY).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2625.
Abstract 2629: Carfilzomib, an irreversible proteasome inhibitor, induces caspase-dependent apoptosis and inhibits the growth of mantle cell lymphoma in vitro and in tumor-bearing SCID mice
Authors: Zhang Liang , Qian Jianfei , Yang Jing , Aujay Monette , Demo Susan , Yi Qing , Wang Michael 
Published: February 2011

Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma subtype with poor clinical outcome. The proteasome is a clinically proven therapeutic target for MCL. Bortezomib is a reversible proteasome inhibitor approved for MCL therapy. Carfilzomib, the new irreversible proteasome inhibitor with the chymotrypsin-like selectivity, has been shown to be effective in multiple myeloma. The objective of our study was to evaluate the therapeutic efficacy of carfilzomib in MCL in vitro and in vivo and to elucidate the mechanism of carfilzomib-mediated cell apoptosis. Four human MCL cell lines, SP53, MINO, Granta 519, and Jeko-1; freshly isolated primary MCL cells from four MCL patients; and normal peripheral blood mononuclear cells (PBMCs) from five healthy donors were treated with carfilzomib. A 3H-thymidine incorporation assay showed that carfilzomib not only inhibited the growth of the MCL cell lines but also freshly isolated MCL cells from patients in a dose-dependent manner. Interestingly, carfilzomib also inhibited the proliferation of PMA/ionomycin or anti-CD3 mAb/anti-CD28 mAb-activated, but not resting PBMCs from healthy donors. Flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that carfilzomib induced apoptosis in both the cell lines and primary MCL cells in time- and dose-dependent manners. Notably, carfilzomib did not induce apoptosis of normal PBMCs. Carfilzomib was also effective and therapeutic in a MCL mouse model established in severe combined immunodeficient (SCID) mice. MINO cells (5 × 106) were inoculated subcutaneously into the right flank of SCID mice. Three weeks later, after palpable tumors developed, mice were treated intravenously with either vehicle alone (10% captisol) or carfilzomib (5 mg/kg) on day 1 and day2, dosing repeated weekly for 5 cycles. Tumor growth was significantly inhibited after carfilzomib treatment compared with vehicle control, and the survival time of tumor-bearing mice was significantly prolonged in the treatment group. Western blot analysis showed that apoptosis of MCL cells was induced through the activation of caspase cascades and PARP pathway. Pretreatment of cells with pan-caspase inhibitor (z-VAD) but not caspase-8 inhibitor (z-IETD) alone or caspase-9 inhibitor (z-LEHD) alone completely blocked carfilzomib-induced apoptosis. In conclusion, carfilzomib inhibited growth and induced apoptosis of MCL cells in vitro and in vivo. Cell apoptosis was induced via caspase-dependent signaling pathway. Our preclinical data indicate that carfilzomib may be used as a therapeutic agent in MCL treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2629.
Abstract 263: p38 MAPK is required for EGFR nuclear translocation
Authors: Hsu Sheng-Chieh , Hung Mien-Chie 
Published: February 2011

Abstract
The epidermal growth factor receptor (EGFR) severs as a mediator of signal cascades on the cell surface and translocates to the nucleus to control many cellular process including transcriptional regulation and DNA repair. However, the molecular mechanisms of EGFR nuclear translocation remain elusive. In this study, we show that, in addition of EGF, nuclear translocation of EGFR was induced by several p38 MAPK activating reagents including UV and cisplatin. The p38 MAPK activation correlated with EGFR nuclear translocation. To further examine the role of p38 MAPK in the EGFR nuclear translocation, p38 MAPK inhibitors, dominate negative p38 MAPK and p38 MAPK siRNA were used to inhibit UV-induced EGFR nuclear translocation. Consequently, EGFR nuclear translocation can be induced by p38 MAPK activator. Thus, we demonstrate here that p38 MAPK is required for EGFR nuclear translocation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 263.
Abstract 2632: Syrbactin, a novel proteasome inhibitor class, induces apoptosis and autophagy in neuroblastoma
Authors: Bachmann Andre S. , Archer Crystal R. , Koomoa Dana-Lynn T. , Clerc Jerome , Shimizu Mariko , Kaiser Markus , Schellenberg Barbara , Dudler Robert 
Published: February 2011

Abstract
Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC50: 0.004 µM) and dexamethasone-resistant MM1.RL cells (IC50: 0.005 µM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC50: 0.015 µM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53, and led to apoptotic cell death. Strikingly, GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser473 and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2632.
Abstract 2634: Combination of HSP90 and mTOR inhibition promotes pancreatic cancer growth inhibition
Authors: Weekes Colin D. , Ciobanu Madalina 
Published: February 2011

Abstract
The molecular determinants of resistance to mTOR targeted therapies remain unspecified. Genomic analysis has demonstrated that a number of gene families promoting intracellular signal transduction are overexpressed in mTOR resistant human pancreas explant xenografts. Heat shock proteins serve as molecular chaperone for many of the proteins implicated in the analysis. As such, it was hypothesized that proximal intracellular signal transduction inhibition with a HSP90 inhibitor could overcome inherent pancreas cancer resistance to mTOR inhibitors. Fourteen human pancreatic cell lines have been analyzed with respect to their proliferative capacity upon exposure to RAD001 (mTOR inhibitor) and AUY922 (HSP90 inhibitor), both as single agents and in combination. In vitro analysis with CalcuSyn® software demonstrates synergistic antiproliferative effects of these two drugs. For example, combination index (CI) values ranging from 0.01 to 0.5 were observed when the mTOR resistant cell line PANC02.03 was treated with the combination of RAD001 and AUY922. In vivo treatment of the L3.6 xenograft model with AUY922 and RAD001 resulted in preferential tumor growth inhibition of the combination relative to either drug alone. These effects were associated with the inhibition of the pI3K/AKT/mTOR and the ERK pathways. In summary, proximal signal transduction inhibition by a HSP90 may overcome inherent pancreas cancer mTOR inhibitor resistance. Future work is designed to extend these finding and to determine the specific pathways that are necessary for the observed growth inhibition.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2634.
Abstract 264: EGFR endocytosis after binding of different ligands
Authors: Grøvdal Lene M. , Henriksen Lasse , Grandal Michael V. , Knudsen Stine LJ , van Deurs Bo 
Published: February 2011

Abstract
The EGF receptor (EGFR) is activated by binding of ligand, leading to both signaling and receptor endocytosis. This endocytosis can lead to receptor downregulation, or recycling. Although EGFR regulation has received much attention, most studies have been performed using either EGF or TGFα. We described EGFR endocytosis upon binding of four additional ligands. Even though all ligands induce internalization, degradation of the receptor is dependent on the nature of the ligand bound. We have shown that the different ligands vary in levels of EGFR activation, receptor ubiquitination, and also in pH-stability of receptor-ligand interaction. We found that whereas HB-EGF and betacellulin are strong inducers of EGFR degradation, TGFα and epiregulin mostly allow for recycling of the EGFR. Amphiregulin also allows for recycling of the EGFR, but by a slower pathway. EGF leads to both recycling and degradation of the EGFR. We now show that, in addition to intracellular sorting in endosomes, the mechanism of internalization of the EGFR from the plasma membrane also differs depending on which ligand is bound.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 264.
Abstract 2642: Identification and characterization of selective inhibitors of ubiquitin specific protease 7
Authors: Reverdy Céline , Conrath Susan , Lopez Roman , Planquette Cécile , Collura Vincent , Guedat Philippe , Delansorne Rémi , Daviet Laurent , Colland Frédéric 
Published: February 2011

Abstract
Regulated protein turnover is primarily controlled by the ubiquitin-proteasome system. The only marketed drug related to the ubiquitin-proteasome system, bortezomib, is acting as a proteasome inhibitor and has been approved for the treatment of some hematological cancers. Targeting the upstream ubiquitin conjugation/deconjugation system carries out promises of therapeutics with increased specificity and selectivity. Ubiquitin-specific proteases (USP) are involved in the deubiquitination of specific target substrates regulating their stability, subcellular localization and/or activation status. USP represent a drugable target class due to their thiol-protease catalytic core which is amenable to pharmacological inhibition by small molecules. A genome-wide RNAi screen of the catalytically active human USPs in cancer-relevant cellular models and phenotypic assays allowed us to identify USP7/HAUSP as promising cancer target. Fluorescence-based screening assays using optimized USP substrates including various ubiquitin derivatives (ubiquitin precursor, branched ubiquitin chains) as well as specific, physiological substrates were developed. High-throughput screening performed on our chemically diverse library followed by different optimization programs resulted in the discovery of several series as novel USP7 inhibitors. Our progress made towards the specificity issue will be presented here with the identification of the first USP7-specific series. These will help further validate this novel class of molecular targets and may provide a structural basis for the development of new anticancer drugs.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2642.
Abstract 2643: A highly versatile nanoplatform for the treatment and imaging of cancers
Authors: Lam Kit S. , Juntao Luo , Xiao Kai , Li Yuan-pei , Lee Joyce , Yao Nianhuan , Xiao Wenwu , Wang Yabg , Kent Michael , Cheng Holland , Xing Li , Liu Gangyu , Tan Yihrong 
Published: February 2011

Abstract
We have recently developed a novel amphiphilic polymer (telodendrimer), comprised of linear polyethylene glycol and cholic acid cluster, that can self-assemble under aqueous condition to form stable micelles. We have succeeded in loading the nanoparticles with several different hydrophobic drugs. These include paclitaxel, etoposide, vincristine, and dexamethasone. This nanoplatform is highly versatile. Particle size can be readily tuned by varying the configuration and composition of the telodendrimer. Nanoparticles of various sizes loaded with DiD, a near infra-red hydrophobic dye, were prepared and their biodistribution evaluated in nude mice bearing ovarian cancer xenografts. Particles smaller than 60 nm preferentially targeted the tumors whereas particles at 150nm were found to concentrate at the liver and lung but with low tumor uptake. The surface chemistry can be easily modified by tethering various acidic or basic peptides to the distal polyethylene glycol tail of the telodendrimers. Undesirable liver uptake was very high for those nanoparticles with high surface charges, either positive or negative. In contrast, liver uptake was very low but tumor uptake was very high when the surface charge was neutral. Ligation of tumor targeting ligands to the particle surface further improved tumor targeting and intracellular uptake at the tumor site. In addition to xenograft models, we have also demonstrated that the nanoparticles could preferentially target early spontaneous mammary tumors of PyV-MT transgenic mice. We have just completed a Phase I study of placiltaxel-loaded nanoparticles in companion dogs with lymphoma and showed that the drug is safe.
The nanoparticles are stable both in vitro and in vivo. Additional stability of the nanoparticles can be achieved by chemical stitching of adjacent telodendrimers after micelle formation. The telodendrimer can be easily radioiodinated with [I-131]-PIB, and the resulting radio-labeled nanoparticles can be used for both radioimaging and radiotherapy. Very recently, we have succeeded in loading the nanoparticles with bortezomib (a proteasome inhibitor) to high level. We are currently evaluating the in vivo anti-tumor activities of the bortezomib nanoformulation in xenograft lymphoma as well as ovarian cancer models in nude mice. This new class of nanotherapeutics shows great promise in future cancer therapy and imaging.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2643.