bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1774: Selection for the EGFR T790M gatekeeper resistance mutation may vary among different small molecule EGFR TKIs
Authors: Chmielecki Juliann , Pietanza Maria C. , Kris Mark , Miller Vincent , Stout Thomas , Pao William 
Published: February 2011

Abstract
Mutations within exons encoding the kinase domain of EGFR confer increased sensitivity of non-small cell lung carcinomas to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Unfortunately, all patients whose disease responds initially to these therapies eventually develop acquired resistance. In ∼50% of cases, resistance is associated with acquisition of a second-site ‘gatekeeper’ mutation within EGFR, T790M. More potent ‘2nd generation’ EGFR inhibitors theoretically able to overcome T790M-mediated resistance have displayed limited clinical success. In preclinical models of acquired resistance, many of these TKIs (HKI-272, BIBW2992, PF00299804) actually select for the emergence of EGFR T790M-harboring clones.
To determine if EGFR TKIs in general lead to the emergence of T790M, we modeled acquired resistance in vitro with the reversible TKI, XL647 (Symphony Evolution, Inc., Rockville, MD), the irreversible EGFR TKI, BIBW2992 (synthesized at MSKCC), and erlotinib. EGFR mutant TKI-sensitive PC-9 cells (lung adenocarcinoma, del E746-A750) were grown with increasing concentrations of XL647 for ∼160 days. Polyclonal resistant (XL-R) cells were derived that proliferated in drug concentrations ∼50-fold higher than the initial IC50. No other secondary mutations within EGFR were detected by direct sequencing, and the T790M mutation was not found using more sensitive mutation detection methods (e.g. SNaPShot; limit of detection ∼5%). By contrast, both BIBW2992- and erlotinib-resistant PC-9 cells (PC-9 BI-R and PC-9 E-R) harbored T790M, as shown by direct sequencing. No resistant cells displayed MET amplification, another known resistance mechanism. Crystal structure data revealed that XL647 binds reversibly within the ATP binding pocket of EGFR T790M with a similar orientation to erlotinib. Therefore, structural differences alone do not readily explain the differential selective pressure for EGFR T790M with gefitinib/erlotinib vs. XL647. Interestingly, PC-9 XL-R cells remained intermediately sensitive to erlotinib. Consistent with the in vitro observations, early clinical trial data revealed that only 1 of 6 patients with EGFR mutant lung cancer harbored T790M after developing acquired resistance to XL647. Furthermore, at least 2 of these patients subsequently derived clinical benefit from single-agent erlotinib. Collectively, these data suggest that the propensity to develop T790M-mediated resistance varies among different TKIs. We are currently exploring why the selective pressure for resistance conferred by XL647 is different from that of other EGFR TKIs.
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 1774.
Abstract 1775: Growth inhibitory effect of PARP inhibitor olaparib in gastric cancer cells
Authors: Im Seock-Ah , Min Ahrum , Hur Hyung-Seok , Yoon Young-Kwang , Song Sang Hyun , Riches Lucy , Knights Charlotte , Han Sae-Won , Oh Do-Youn , Wombwell Helen , Kim Tae-You , Gu Yi , Lau Alan , Bang Yung-Jue , O'Connor Mark 
Published: February 2011

Abstract
Background Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)is the member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Olaparib (KU-0059436; AZD2281) is a potent oral inhibitor of PARP currently in clinical development, which has selective antitumor activity in cancers, associated with BRCA1 and BRCA2 mutations. Gastric cancer is the most common cancer and the second leading cause of cancer deaths in Korea. New therapies including molecular targeting agents are eagerly awaited, and treatment strategies to overcome chemoresistance are also needed in the treatment of gastric cancer. Materials and Methods We studied the growth inhibitory effects of Olaparib on gastric cancer (GC) cells using clonogenic survival assays and studied the effect of combination with chemotherapeutic agents using MTS assays. Cell cycle analysis and molecular changes induced by olaparib were also performed. Results Olaparib showed marked growth inhibitory activity against the SNU 601 cell line, with IC50 value of 0.015 μM. In addition, 5 out of 11 GC cells (45%) were sensitive to olaparib with IC50s ≤ 2μM. Olaprib induced G2/M cell cycle arrest and apoptosis in sensitive GC cells. We identified synergistic growth inhibitory effects of Olaparib in combination with clinically relevant cytotoxic agents (5-FU, cisplatin, and oxaliplatin). Furthermore, Olaparib-induced apoptosis was associated with PARP cleavage and caspase-3 activation. Conclusion: Olaparib showed growth inhibitory activity against GC cells as a single agent and acted synergistically with cytotoxic agents. These results provide a rationale for the future clinical trials of olaparib combined with cytotoxic drugs in the treatment of gastric 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 1775.
Abstract 1782: Detection of T790M gefitinib resistance mutation in EGFR using the BEAMing method
Authors: Taniguchi Kazuya , Nishitani Kimiyoshi , Okami Jiro , Kodama Ken , Higashiyama Masahiko , Kato Kikuya 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, are effective therapies for non-small cell lung cancer (NSCLC) patients with primary EGFR mutations. However, most patients who initially respond to treatment with these drugs will develop resistance to EGFR TKIs. The secondary EGFR T790M mutation is reported to correlate with acquired resistance. We examined the T790M mutation in primary tumors with BEAMing (beads, emulsion, amplification, magnetic), which is the most sensitive technique to detect minor mutated alleles. Currently, we can detect point mutation at the level of 1/10,000 using an improved version of the BEAMing. We detected T790M mutant alleles in NSCLCs in 19 out of 270 NSCLCs with primary EGFR mutations. The detection of small fraction of T790M mutant alleles may be useful for predicting resistance of NSCLCs to TKIs.
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 1782.
Abstract 1784: Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations
Authors: Yeo Wee-Lee , Riely Gregory J. , Kris Mark G. , Tenen Daniel G. , Pao William , Kobayashi Susumu , Costa Daniel B. 
Published: February 2011

Abstract
Introduction: The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are active in non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. The usual clinical dose of gefitinib (250 mg/day) is only one third of its maximum tolerated dose (MTD), while the dose of erlotinib (150 mg/day) is at its MTD. In NSCLC cell lines both TKIs have similar micromolar (μM) inhibitory concentrations. We explored if erlotinib at 25 mg/day (presumed trough serum concentration similar to gefitinib 250 mg/day at around 0.5 μM) would be active in EGFR mutated NSCLC.
Methods and Patients: To study inhibitory concentrations of gefitinib and erlotinib, we studied EGFR mutated cell lines (HCC827, H3255, PC-9, H1975) exposed to increasing concentrations of these TKIs. Further on, we performed a retrospective evaluation of seven patients with advanced EGFR mutated (exon 19 deletions and L858R) NSCLC that were given erlotinib at 25 mg daily as their first EGFR TKI.
Results: In EGFR mutated cell lines, both gefitinib and erlotinib had median IC50 inhibitory concentrations with similar values and statistical correlation (Pearson r = 0.9999, p &lt; 0.0001). Concordance between the IC50 of gefitinib and erlotinib was confirmed using a separate published dataset of 8 EGFR-mutant NSCLC lines (r = 0.9919, p &lt; 0.0001). These results indicate that both EGFR inhibitors have similar inhibitory concentrations in EGFR mutated cells. Of the 7 patients treated with erlotinib 25 mg/day, 5 (71.5%) had partial radiographic responses. Median progression-free survival (PFS) was 17 months, and individual PFS exceeds 6 months in most patients that have received drug for at least that period. Toxicities were minimal with only 2 (28.5 %) patients having a rash (grade 1) and none (0%) experiencing diarrhea.
Conclusions: In patients with EGFR activating mutations, a dose of erlotinib 25 mg/day leads to impressive response rate and PFS similar to the growing experience with gefitinib 250 mg/day and erlotinib 150 mg/day. Identifying prospectively the clinically-active dose ranges of erlotinib and gefitinib will help further personalize care for patients with tumors harboring EGFR mutations.
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 1784.
Abstract 1789: NFKBIA deletion in malignant gliomas
Authors: Bredel Markus , Yadav Ajay , Renfrow Jaclyn , Scholtens Denise , Chandler James , Bredel Claudia , Tagge Michael , Lukac Paul , Robe Pierre , Vogel Hannes , Scheck Adrienne , Aldape Kenneth , Chakravarti Arnab , Harsh Griffith 
Published: February 2011

Abstract
Introduction:
Aberrant activation of the Epidermal Growth Factor Receptor (EGFR) oncoprotein is a molecular hallmark of glioblastomas. Two-thirds of tumors with excessive EGFR activation show alteration of the EGFR gene. The mechanism of deregulation of EGFR in the other third remains poorly understood. Nuclear factor of κB inhibitor alpha (NFKBIA) is a potential tumor suppressor.
Methods:
Multidimensional molecular profiles for NFKBIA and EGFR and clinical profiles of 732 malignant glioma patients from multiple academic institutions, The Cancer Genome Atlas Pilot Project, the Repository of Molecular Brain Neoplasia Data, and a randomized phase III trial of temozolomide. NFKBIA mutational and functional analyses in a glioblastoma cell model.
Results:
We found that about 25% of glioblastomas harbor heterozygous NFKBIA gene deletions at chromosome 14q13. NFKBIA functions as a haploinsufficient tumor suppressor in glioblastomas by terminating EGFR signaling. Tumors with NFKBIA deletion lacked EGFR amplifications, indicating functional redundancy of both genetic events in glioblastoma pathogenesis. Loss of NFKBIA gene dosage was significantly associated with briefer patient survival. Patients with low NFKBIA expression had a significantly worse outcome than patients with intact NFKBIA expression. NFKBIA expression was also significantly associated with patient survival in subsets of tumors with unmethylated promoter of the O6-methylguanine DNA methyltransferase (MGMT) gene. A combined outcome predictor model of NFKBIA and MGMT proved highly predictive of duration of survival.
Conclusion:
Deletion of NFKBIA is an alternative mechanism for tumorigenic increase in EGFR signaling in glioblastomas. NFKBIA inactivation is associated with shorter survival of patients with malignant gliomas.
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 1789.
Abstract 179: Identification of novel targets for aberrant methylation in pancreatic cancer by a newly developed method “methyl-CpG targeted transcriptional activation (MeTA)”
Authors: Fukushige Shinichi , Shimizu Hideyuki , Sato Yuko , Horii Akira 
Published: February 2011

Abstract
Identification and characterization of genes selectively hypermethylated in cancer may improve our understanding of the role of epigenetic alterations in tumorigenesis. In addition, genes frequently methylated in a tumor-specific manner could be used as tumor markers. DNA methylation inhibitors such as 5-aza-cytidine or 5-aza-2’-deoxycytidine have been widely used to search epigenetically silenced genes. However, these inhibitors frequently upregulate genes whose promoters remain unmethylated. We tried to improve the specificity and sensitivity in detecting methylation-mediated silenced genes in cancer and successfully developed a new method termed “methyl-CpG targeted transcriptional activation (MeTA)” by using a transcriptional activating fragment with a methyl-CpG binding domain (MBD). Because MBD proteins in fact mediate transcriptional repression of tumor suppressor genes associated with promoter hypermethylation in cancer, MeTA is thought to be one of the ideal methods to search such genes. In the preliminary experiments using human embryonic kidney cell line 293T, we found that the combination of MeTA with gene expression microarray is useful; genes containing CpG islands can be efficiently identified (93.5% by MeTA vs. 66.8% by 5-aza-cytidine) even those that are difficult to find by the conventional DNA methylation inhibitors. We applied this method to twelve typical pancreatic cancer cell lines with a normal pancreatic ductal epithelial cell line HPDE as the control, and have searched for genes commonly upregulated after MeTA. Thirty-one genes were upregulated by two-folds or more in six pancreatic cancer cell lines or more. Among these, 26 genes have not been reported previously using the conventional DNA methylation inhibitors. Methylation statuses of three genes, NEFL, NEFM, and IRX4 were further examined by methylation-specific PCR and found that these three genes were aberrantly methylated in all of the analyzed tumors, 11 resected primary pancreatic cancer specimens and 22 pancreatic cancer cell lines. Our results suggest that “MeTA” is a highly efficient method to identify methylation-mediated transcriptionally silenced genes in human pancreatic cancer and that this method can be applied to other types of human 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 179.
Abstract 1794: TXNL2 is a key regulator of reactive oxygen species levels and NF-κB activity in cancer cells
Authors: Qu Ying , Wang Jinhua , Shin-Sim Miyung , Huang Jiang , Liu Bingya , Zhang Ning , Cui Yukung , Giuliano Armando E. , Cheng Ninghui , Cui Xiaojiang 
Published: February 2011

Abstract
Cancer cells usually generate and maintain higher levels of reactive oxygen species (ROS) compared to normal cells, in part because of their higher metabolic rate and defects in the electron transport chain. Because most tumor cells possess stronger antioxidative defense mechanisms to counterbalance excessive ROS, redox proteins such as thioredoxins (TRXs) and glutaredoxins (GRXs) are potential targets of anticancer therapy. We recently found that a novel redox protein called thioredoxin-like 2 (TXNL2) is required for embryonic stem cell functions and is consistently overexpressed in many different cancers. It has a TRX-homology domain and two GRX-homology domains, suggesting that it may have redox function.
Using immunohistochemical and cDNA microarray analyses, we found that levels of TXNL2 were significantly higher (P = 0.00036) in human breast cancers than in normal breast tissues; levels also were higher in human breast cancer cell lines than in normal mammary epithelial cell lines. Knockdown of TXNL2 by shRNA in breast cancer cell lines induced a 5-fold increase of ROS levels and inhibited cell proliferation, survival, invasion, and the expression of genes critically involved in these cellular processes. Breast cancer stem-like cell populations and stem-like properties such as mammosphere formation were reduced by TXNL2 silencing and induced by TXNL2 overexpression. Surprisingly, TXNL2 depletion in normal mammary epithelial cells did not significantly affect ROS levels and cell survival. Xenograft models of orthotopic injection indicated that TXNL2 knockdown inhibited mammary tumor growth and metastasis to the lung. Cell signaling studies showed that TXNL2 knockdown inhibited GSH synthase (GSS) expression, and thereby decreased GSH levels and increased ROS levels; N-acetylcysteine (NAC), a GSH precursor, partially reversed these effects. In addition, TXNL2 knockdown suppressed NF-κB activity by inactivating IKK and p65 via glutathionylation, whereas TXNL2 overexpression markedly increased NF-κB activity. Blockade of NF-κB using its small-molecule inhibitors and IκB overexpression mimicked the effect of TXNL2 depletion.
Our results suggest that TXNL2 is a potentially promising target for ROS-based anticancer therapies and is a key regulator of the NF-κB pathway. Because high cellular antioxidant capacity is well-known to impair cellular responses to chemotherapy and radiation therapy, our study may also open up a new avenue of maximize the efficacy of conventional anticancer therapies by targeting TXNL2.
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 1794.
Abstract 1795: The Combination of Paclitaxel and Gefitinib Inhibits Endometrial Cancer Cells by Inducing Mitotic Catastrophe: Proof of Principle for Dual Therapy in Endometrial Cancer
Authors: Meng Xiangbing , Laidler Laura L. , Albitar Lina , Holmes Anna M. , Dai Donghai , Buekers Thomas E. , Bender David P. , Leslie Kimberly K. 
Published: February 2011

Abstract
Serous uterine endometrial cancer is a lethal disease for which new therapeutic regimens are urgently needed. Combinations of chemotherapeutic agents and small molecule growth factor inhibitors have demonstrated activity in cancers from other sites. Our objective was to determine whether such a combination could be active in serous endometrial cancer cells. The effects of the EGFR inhibitor gefitinib (ZD1839, Iressa) alone, paclitaxel alone, and the combination of both agents on the cell cycle and on cell proliferation were studied using Hec50co cells, a validated model for type II serous endometrial cancer with absent p53. First, we established the IC50 for paclitaxel alone (14 nM) compared to that of paclitaxel and gefitinib in combination (1.3 nM). This 10-fold reduction in the IC50 with dual therapy yielded a combination index of 0.25, strongly suggesting that the paclitaxel and gefitinib combination resulted in synergistic growth inhibition. Sixty-seven percent of the cells treated with paclitaxel and gefitinib arrested in the G2/M phase. This arrest of the cell cycle at G2/M with combination therapy was significantly greater than with single agent treatment alone (p &lt; 0.001) and was associated with inhibition of p38 phosphorylation and the induction of CDC25C phosphatase and Cyclin B1. When induced, these factors abrogate the G2/M checkpoint and result in rapid, premature progression to M phase; this mechanism is particularly active in the setting of absent p53. With rapid progression into M, the cells were highly sensitive to paclitaxel and were killed by the mechanism of mitotic catastrophe. Similar findings were observed in the same cells treated with the combination of paclitaxel and a specific inhibitor of p38, SB203580. Our study suggests that inhibition of EGFR or downstream p38 pathway can abrogate the mitotic stress checkpoint induced by cytotoxic agents targeting microtubules such as paclitaxel. These findings suggest a new therapeutic strategy for the treatment of serous endometrial carcinoma worthy of clinical confirmation.
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 1795.
Abstract 180: Potential utility of Reprimo methylation as a sensitizer to anticancer treatment in gastric cancer
Authors: Akira Ooki , Yamashita Keishi , Watanabe Masahiko 
Published: February 2011

Abstract
Introduction: Reprimo is a highly glycosylated protein, inducing cell cycle G2 arrest. Reprimo promoter methylation has been reported as the mechanism regulating its expression in gastric cancer, but the biological roles remain unclear. The aim of this study is to examine Reprimo from a functional point of view.
Methods: The methylation status of Reprimo promoter was analyzed using quantitative-methylation specific polymerase chain reaction (Q-MSP), and the effects of expression were examined in gastric cancer cell lines (AZ521 and SH10) with no endogenous expression of Reprimo using stable transfection and phenotype analysis (WST assay and apoptosis assay).
Results: Reprimo methylation was detected in 6 of 8 gastric cancer cell lines; the silenced or reduced expression could be restored by treatment with demethylating agents such as 5-aza-2’-deoxycitidine and/or trichostatin A. On Q-MSP, the optimal cutoff value (0.42) determined by the receiver operating characteristic (ROC) curve could significantly discriminate primary tumor (69%, 57/83) from the corresponding normal tissues (18%, 15/83, P&lt;0.0001). AZ521 cells with enforced expression significantly enhanced sensitivity to 5-FU therapy, and augmented apoptosis without affecting cell cycle. On the other hand, SH10 cells without methylation exhibited the undetectable level of endogenous expression, and Reprimo expression was robustly induced under 5-fluorouracil (5-FU), one of the standard anticancer agents for gastric cancer. As a result, SH10 cells stably transfected with Reprimo exhibited similar level apoptosis with mock cells.
Conclusion: Reprimo expression is inducible under 5-FU agent, that may lead to apoptosis in gastric cancer. However, its expression is frequently suppressed by promoter methylation. Thus, Reprimo methylation status is considered to have a great potential as a predictive biomarker to select patients who may be effective for 5-FU therapy in gastric 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 180.