bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3652: HDAC inhibitors activate NF-κB in human leukemia cells through an ATM/NEMO-dependent DNA Damage-related pathway
Authors: Rosato Roberto R. , Kolla Sarah S. , Hock Stefanie K. , Almenara Jorge A. , Atadja Peter , Dent Paul , Grant Steve 
Published: February 2011

Abstract
The ability of HDAC inhibitors (HDACIs) to induce sustained activation of NF-κB (p65/RelA) has been attributed to reversible RelA acetylation (Chen et al., Science 293:1653-7, 2001), a phenomenon that diminishes HDACI antineoplastic activity (Dai et al., Mol Cell Biol. 25:5429-44, 2005). However, the process by which HDACIs initially activate NF-κB has yet to be elucidated. To address this question, mechanisms underlying HDAC inhibitor (HDACI)-mediated NF-κB activation were investigated in human myeloid leukemia cells. Exposure of U937 and other leukemia cells to the pan-HDACI LBH-589 induced reactive oxygen species (ROS) and p65/RelA activation, the NF-κB-dependent induction of Mn-SOD2 mRNA and protein accompanied by ROS elimination, and sequential induction of XRCC1 (single strand) followed by γ-H2A. X (double strand) DNA breaks. LBH-589 lethality was significantly attenuated by siRNA knockdown of the chromatin-linked DNA damage protein histone H1.2. U937 IκBα super-repressor cells lacking serine 32 and 36 IκBα phosphorylation sites displayed diminished HDACI-mediated NF-κB activation/Mn-SOD2 induction, accompanied by enhanced ROS accumulation, DNA damage, and apoptosis. In contrast, TRAF2 siRNA knockdown blocked TNFα- but not HDACI-mediated NF-κB activation and lethality. The Mn-SOD2 mimetic TBAP prevented HDACI-induced NF-κB activation and nuclear localization, while dramatically attenuating DNA damage and apoptosis. Notably, LBH-589 exposure activated ATM (on serine 1981) and increased its association with NEMO, events comprising a recently described “inside-out” nuclear NF-κB activation pathway (Wu et al., Science 311:1110-1, 2006). Notably, siRNA NEMO or ATM knockdown blocked HDACI-mediated NF-κB nuclear translocation/activation, diminished MnSOD2 induction, and potentiated oxidative injury, DNA damage and cell death. Similarly, SUMOylation-site mutant NEMO (K277A and/or K309A) cells exposed to LBH-589 displayed diminished association of ATM with NEMO, reduced NEMO and p65/RelA nuclear localization/activation, and MnSOD2 down-regulation. These events were accompanied by increased ROS production, γ-H2A. X formation, and enhanced lethality. Collectively, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-κB pathway through an ATM/NEMO-dependent process involving the induction of ROS and DNA damage. They also raise the possibility that blocking NF-κB activation via the atypical DNA damage-related ATM/NEMO nuclear pathway has the potential to enhance HDACI antileukemic activity.
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 3652.
Abstract 3679: Targeting drug-resistant GIST cells with a quadruplex-binding small molecule
Authors: Gunaratnam Mekala , Collie Gavin , Reszka Anthony , Todd Alan , Parkinson Gary , Fletcher Jonathan , Neidle Stephen 
Published: February 2011

Abstract
Gastrointestinal tumours (GIST) originate, at least in part, from disregulation and consequent aberrant expression of the c-kit oncogene. Imatinib is an effective inhibitor of the ATP-binding activity of the kinase domain in the c-kit protein, and is used clinically to treat GIST patients. However acquired resistance to Imatinib is a severe problem hindering long-term patient survival. We have previously reported on an alternative approach to c-kit therapy that involves targeting and stabilising quadruplex DNA sequences with a small molecule, (i) in two sequences within the c-kit promoter so that c-kit expression is down-regulated, and (ii) in the single-stranded overhang of telomeric DNA, inhibiting telomerase activity in GIST cells. We have previously reported that both of these are targeted by a potent (IC50 ≪ 1μM) tetra-substituted naphthalene diimide compound in the Imatinib-sensitive GIST882 patient-derived cell line.
This compound is equally potent in the patient-derived GIST48 Imatinib-resistant line; we report here that it has no effect on c-kit expression, telomerase activity, or the expression of other oncogenes in which promoter quadruplexes have been identified. Instead we find that the translation of the apoptosis-related bcl-2 gene is profoundly affected, but not its transcription. The bcl-2 gene has a potential quadruplex-forming region in the 5′-UTR sequence, and we report here that this forms a stable RNA quadruplex structure, which is further stabilised by the binding of the naphthalene diimide ligand. A reporter assay approach using a dual luciferase psiCHECK-2 vector, containing the bcl-2 5′-UTR sequence, is being used to validate the key concept that this G-rich sequence is involved in modulating translation in vitro, and in vivo through transfection into mammalian cells. Our current experiments in an Imatinib-resistant GIST cell line in the presence of the compound are enabling us to substantiate this cellular target and characterize the mode of action.
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 3679.
Abstract 3690: Development of a cell based high-throughput assay for drug discovery to treat ovarian cancer
Authors: Arslan Ahmet D. , He Xiaolong , Beck William T. 
Published: February 2011

Abstract
PTBP1 (polypyrimidine tract-binding protein, PTB) is a 59.6-kD nuclear protein involved in pre-mRNA splicing. Its molecular functions include regulation of alternative splicing (AS) and internal ribosomal entry site (IRES)-mediated translation. Our previous work revealed that PTB was overexpressed in human ovarian tumors and that knockdown of PTB expression by shRNA impaired ovarian tumor cell growth and malignant properties in vitro (Oncogene 26:4961-68, 2007). We have also observed slower tumor growth in a xenograft mouse model of ovarian cancer when PTB was knocked down (unpublished). These data suggest that PTB is a novel therapeutic target. To attempt to identify small molecules that have potential to act as shRNA and inhibit PTB, we have designed a cell-based high-throughput screening (HTS) system that allows fast and reliable detection of small molecule inhibitors of PTB protein activity that have potential to alter mRNA splicing. Our approach is based on differential splicing of a PTB target gene (identified by microarray analysis) at different levels of PTB activity in the cell. We have subcloned exons 14 - 16 of one of these PTB targets, Gamma-aminobutyric acid type B receptor 1 (GABBR1, upstream of two different fluorescent markers; the resulting two minigenes were designated “Gred” [short form], and “Ggreen” [long form]). We further verified that the splicing of the minigenes is dependent on the PTB level in the cells. We are presently establishing stable reporter cell lines expressing both minigenes, and validating their compatibility for HTS assay by measuring the stability of fluorescence protein expression over time and response to known PTB inhibitory stimuli (e.g. PTBshRNA). Optimization for HTS includes testing cell seeding density, DMSO tolerance, pilot experiments with specific chemical libraries, data analyses, and verification of “hits” in vitro, followed by pilot HTS with small libraries of chemical diversity to determine if any of these agents will block the activity of PTB. Since overexpressed PTB plays an integral part in maintaining ovarian tumor cell growth and malignant properties, identification of small molecule PTB inhibitors by this approach may uncover novel drugs for the treatment of ovarian and possibly other cancers.
(Support in part by grants RO1 CA40570 and RO1 CA138762 (to WTB), by OCRF (to XH), and by UIC.
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 3690.
Abstract 3696: Pharmacokinetics (PK) of XMT-1001, a novel polymeric prodrug of camptothecin, in mice bearing HT-29 human colon carcinoma xenografts
Authors: Walsh Mark D. , Hanna Suzan K. , Sen Jeremy M. , Benson John D. , Cabral Carolina B. , Yurkovetskiy Alex , Lowinger Timothy B. , Zamboni Beth A. , Zamboni William C. 
Published: February 2011

Abstract
Introduction: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT prodrug, CPT is conjugated with a ∼60 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal) (PHF). Dual-phase release of CPT from XMT-1001 occurs via lipophilic intermediates, CPT-20-O-(N-succinimido-glycinate) (CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate) (CPT-SA). Hydrolysis of intermediates results in formation of an active-lactone form of CPT. XMT-1001 is designed to produce a prolonged exposure in plasma and tumor and to improve CPT's therapeutic index. We evaluated plasma, tumor and tissue PK of XMT-1001, CPT-SI, CPT-SA and CPT in mice bearing HT-29 human colon cancer xenografts.
Methods: XMT-1001 was administered at 60 mg CPT equivalents/kg IV x 1 via a tail vein. Mice (n = 3) were sacrificed at 0.083 to 24, 48, 72, 168 and 336 h after administration. Plasma, tumor and tissue samples were processed to measure the total (lactone + hydroxy acid) forms of XMT-1001, CPT-SI, CPT-SA and CPT via LC-MS/MS. Area under concentration versus time curves (AUC0-t) and time of last detectable concentration (TLast) were calculated.
Results: PlasmaTumorLiver AUC0-t (ng/mL·h)TLast (h)AUC0-t (ng/mL·h)TLast (h)AUC0-t (ng/mL·h)TLast (h)XMT-10013,639,034168138,156336663,493336CPT-SI53,653248,85033613,239336CPT-SA46,010241,59516814,063336CPT8,86024853481,11616
Conclusions: CPT conjugation to the polymer carrier, PHF, provides a water soluble formulation with potential advantages of extended systemic exposure to the conjugated drug XMT-1001, conjugated release products CPT-SI and CPT-SA, and active drug CPT. After XMT-1001 administration, the majority of plasma exposure is accounted for by conjugated CPT. The analysis of XMT-1001 revealed substantial tumor and tissue accumulation and extended exposure of conjugated drug and conjugated release products CPT-SI, CPT-SA and CPT. The improved tumor distribution and extended localized release of small molecule prodrugs and active CPT by XMT-1001 are hypothesized to improve safety and efficacy over existing drugs of the same class.
Supported by Mersana 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 3696.
Abstract 3717: Randomized phase II trial of cladribine with or without immediate rituximab for newly diagnosed or previously treated hairy cell leukemia to eliminate minimal residual disease: Interim report
Authors: Kreitman Robert J. , Noel Pierre , Yuan Constance M. , Raffeld Mark , Stetler-Stevenson Maryalice 
Published: February 2011

Abstract
Purine analogs including cladribine can induce complete remission (CR) in a high percentage of patients with previously untreated hairy cell leukemia (HCL), but late relapses are common and disease-free survival curves show no convincing evidence of cure. Many patients in CR after cladribine have minimal residual disease (MRD) which strongly expresses CD20, and the anti-CD20 Mab rituximab, particularly with a purine analog, can eliminate MRD to undetectable levels. To determine the potential benefit of adding rituximab to cladribine for initial or 2nd-line treatment of HCL, a randomized trial was begun in 150 HCL patients with 0-1 prior courses of cladribine requiring therapy. Patients receive cladribine 0.15 mg/Kg by 5 daily 2-hr i.v. infusions, and 8 weekly i.v. infusions of rituximab 375 mg/m2. Rituximab in half the patients is begun with the 1st dose of cladribine, and in the other half is delayed at least 6 months when MRD is detectable in blood. Endpoints include determining whether MRD rates are lower at 6 months with immediate rituximab, and whether blood MRD-free survival is longer when rituximab is delayed at least 6 months or begun with cladribine. HCL variant (HCLv) patients, known to respond poorly to initial cladribine alone, are not randomized and receive rituximab with cladribine. Bone marrow and blood are assessed for MRD by immunohistochemistry, PCR and flow cytometry at 1 and 6 months after cladribine. At this time 14 patients are enrolled, including 6 untreated and 8 with 1 prior course of cladribine, the latter group including 1 with HCLv. So far, the overall response rate is 100% with 10 (83%) CRs in 12 evaluable patients at 61-243 (median 202) days of follow-up. By 1 month, 0 of 5 patients after cladribine alone vs 5 (71%) of 7 after cladribine with immediate rituximab were MRD-free (p=0.028), including the patient with HCLv. Neutropenic fever was more frequent in patients receiving immediate rituximab, and was associated with both infusional reactions and reversible infections. We conclude that rituximab with cladribine can result in early clearing of MRD which is frequently present after cladribine alone. Additional accrual and follow-up is needed to determine whether simultaneous cladribine and rituximab can reduce MRD rates at 6 months, whether MRD-free survival might be longer or shorter with delayed rituximab, and whether rituximab added to cladribine for 1st or 2nd line treatment of HCL can prevent or delay clinical relapse.
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 3717.
Abstract 3720: Encouraging activity of bicalutamide and everolimus in castration-resistant prostate cancer (CRPC): Early results from a phase I/II clinical trial
Authors: Zhang Hongyong , Wang Yu , Ghosh Paramita , Lara Primo N. , Pasquinelli Patricia , Beckett Laurel , deVere White Ralph W. , Pan Chong-Xian 
Published: February 2011

Abstract
Background: Multiple signaling pathways are involved in the development of CRPC. We previously showed that the mTOR pathway is activated in CRPC cell lines while inhibition of this pathway results in upregulation of androgen receptor (AR) signaling (Wang et al, Oncogene. 2008). Simultaneous blockade of the mTOR and AR pathways synergize in inducing PCa cell death and delaying tumor formation in mouse models. We hypothesize that simultaneous blockade of the AR and mTOR pathways in CRPC patients with bicalutamide and everolimus will result in improved efficacy compared to bicalutamide alone.
Methods: A phase II clinical trial with a lead-in safety phase was designed to determine the efficacy and tolerability of the bicalutamide and everolimus combination in CRPC patients compared with bicalutamide alone. Patients must have histologically confirmed disease and demonstrated disease progression (either by PSA or radiographically) while on androgen deprivation therapy. At the lead-in phase, all patients receive both agents. At the phase II stage, patients are randomized to bicalutamide +/− everolimus. The primary endpoint is PSA response. The second endpoints include progression-free survival, time-to-treatment failure, overall survival and toxicity. Here, we report the results of the lead-in phase.
Results: To-date, 13 patients have been screened and 8 have been enrolled with the age ranging XX-XX, and performance status of ECOG 0-1. In the lead-in phase, bicalutamide + everolimus has been well tolerated with no unexpected toxicities. One patient developed grade 3 interstitial pneumonitis (attributed to everolimus) that improved with dose reduction and steroid treatment. Seven of 8 patients have had either stable PSA or a PSA response after at least 8 weeks of therapy. Tumor and blood specimens are being collected for molecular correlative studies of mTOR pathway markers. Conclusions: Thus far, the rational combination of bicalutamide and everolimus appears to have promising anti-tumor activity and an acceptable toxicity profile. The randomized phase of the clinical trial is currently ongoing and will be reported. (Supported by Novartis)
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 3720.
Abstract 373: Circulating endothelial cell measurement allows early prediction of outcome in patients with metastatic colorectal cancer treated with first-line bevacizumab and chemotherapy. Findings from the FNCLCC ACCORD 13/0503 randomized phase II trial
Authors: Boige Valerie , Mendiboure Jean , Adenis Antoine , Boucher Evelyne , Pierga Jean-Yves , Francois Eric , Conroy Thierry , Pignon Jean-Pierre , Ducreux Michel , Farace Françoise , Malka David 
Published: February 2011

Abstract
Purpose - There is no validated biomarker to predict the efficacy of bevacizumab. We tested the hypothesis that circulating endothelial cells (CEC) levels could predict clinical outcome of metastatic colorectal cancer (mCRC) patients starting treatment with bevacizumab and chemotherapy.
Patients and Methods - Among the 145 mCRC patients treated with first-line bevacizumab and irinotecan-based chemotherapy (either FOLFIRI or XELIRI regimen) in the FNCLCC ACCORD 13/0503 randomized phase II trial, 99 agreed to blood sampling at day [D]1 (before treatment) and D15 or 22 (at the end of cycle 1). CEC (CD45-CD31+CD146+7-amino-actinomycin- cells) were quantified by four-color flow cytometry according to a previously validated method. We assessed whether D1 or D15/22 CEC levels, or changes in CEC levels between D1 and D15/22, correlated with patient characteristics, 6-month objective response rate (ORR), and 6-month progression-free survival (PFS) rate (the trial primary endpoint).
Results - CEC levels were higher at D1 in patients with altered PS (p=0.02). CEC levels were higher at D15/22 in the absence of objective response (p=0.04), and at D1 (p=0.01) and D15/22 (p=0.03) in patients whose disease progressed within 6 months of treatment. The best outcome (6-month PFS rate, 96%) was observed in patients with low CEC levels at D1 and D15/22 (cutoff, baseline median=16/mL) compared to patients with high CEC levels at either D1 or D15/22 (79%) and patients with high CEC levels at D1 and D15/22 (68%; trend test, p=0.01).
Conclusions - CEC levels may help in early prediction of efficacy of first-line bevacizumab and chemotherapy in mCRC patients.
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 373.
Abstract 3730: Akt activity is suppressed by doxorubicin through downregulation of ErbB receptors and its enhanced activity is associated with higher sensitivity to doxorubicin in breast cancer
Authors: Harada Amane , Suminaka Chihiro , Oyama Tomoko , Gohda Keigo , Ishihara Hideki , Kim Seung Jin , Noguchi Shinzaburo 
Published: February 2011

Abstract
Anthracyclines are the backbone of breast cancer therapy and benefit patients in both the adjuvant and metastatic setting whereas they are effective for 50-60% of breast cancer patients and cause substantial morbidity and occasional life-threatening toxic effects. For these reasons, it has been eagerly anticipated to develop diagnostic markers which can predict efficacy of the treatment. HER2 amplification or overexpression of its protein (HER2 positivity) has been shown to be associated with relative benefit from anthracycline-based chemotherapy (Gennari A. et al., J. Natl. Cancer Inst, 100, 14-20, 2008). However, HER2 is positive in 15-25% of breast tumor tissues and no clear biological mechanism between HER2 positivity and action of anthracyclines has been reported.
In this study, we have shown that doxorubicin exerts its anti-tumor activity through inhibiting ErbBs-Akt signal pathway. Promoted activity of Akt was associated with not only HER2 but EGFR overexpression and responsiveness to doxorubicin in human breast cancer cell lines. As well as doxorubicin, PI3 kinase inhibitor caused growth inhibition and apoptosis in cells with promoted Akt activity more significantly than cells with weakly activated Akt. Doxorubicin-induced cytotoxic stress induced internalization and degradation of ErbBs followed by inactivation of Akt. This was confirmed with the observation that doxorubicin caused decrease in the amount of immunocomplex formed between HER3 and p85, PI3 kinase regulatory subunit. These data indicate that cancer cells with ErbBs overexpression and promoted Akt activity are dependent on activities of these factors for their growth and survival, and doxorubicin inhibits the ErbBs-Akt signal pathway through inducing downregulation of ErbB receptors. Furthermore, we found that highly phosphorylated Akt in tumors corresponds to improved recurrence-free survival in breast cancer patients treated with anthracycline-based adjuvant chemotherapy relative to weakly phosphorylated Akt. Taken together, we provide mechanistic insight into molecular basis of correlation between HER2 positivity and sensitivity to anthracyclines, and propose a new possibility that Akt activity is a useful predictor of response to anthracycline-based chemotherapy.
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 3730.