bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 69: Genomic deletions clustered on chromosomes 8 and 9 are associated with pancreatic cancer progression
Authors: Sinha Arkadeep , Lenkiewicz Elizabeth , Barrett Michael , Haab Brian B. 
Published: August 2012

Abstract
Pancreatic cancer cells that have mesenchymal traits can be particularly migratory and resistant to chemotherapeutics. These cells are presumed to represent a more advanced and deadly population of cells relative to cancer cells with more differentiated, epithelial traits. The factors leading to the acquisition of a mesenchymal phenotype in pancreatic cancer are not well characterized. In this study, we tested the hypothesis that the development of a mesenchymal phenotype occurs selectively in tumor cells that harbor specific enabling genomic alterations. As a model system, we used pancreatic cancer cell lines that had either an epithelial-like or a mesenchymal-like phenotype when cultured in vitro, as defined by morphology and key molecular indicators. We used whole-genome comparative genomic hybridization to compare the genomic amplifications and deletions between 17 epithelial-like cell lines and 9 mesenchymal-like cell lines. An unbiased search revealed that 18 genes (each comprising at least three contiguous probes in a coding region) had alterations in a significantly greater percentage of the mesenchymal-like cells than the epithelial-like cells, whereas no genes had more frequent alterations in the epithelial-like cells. Sixteen of the 18 alterations were deletions, and 14 of the deletions were clustered in specific regions on chromosomes 8 and 9, suggesting the importance of those regions for suppressing de-differentiation. Some of the 18 genes were previously identified in studies of pancreatic cancer, such as SGCZ, KIAA1797 and SMAD4, while others were not. Certain genes showed a good correlation between DNA copy number and mRNA expression, providing evidence for the functional importance of those alterations. The known functions of the 18 genes include cell cycle control, cell membrane homeostasis, immune system regulation, and TGF-β pathway transduction, the deletion of which might provide improved survival advantage and cell structure modification required for metastasis. These findings support the concept that mesenchymal-like cancer cells are genetically more progressed than their epithelial-like counterparts and provide leads on the genomic hits that enable such progression.
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 69. doi:1538-7445.AM2012-69
Abstract 7: Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers
Authors: Soh Junichi , Shien Kazuhiko , Ueno Tsuyoshi , Tsukuda Kazunori , Suda Kenichi , Kubo Takafumi , Furukawa Masashi , Muraoka Takayuki , Maki Yuho , Tanaka Norimitsu , Yamamoto Hiromasa , Kiura Katsuyuki , Mitsudomi Tetsuya , Toyooka Shinichi , Miyoshi Shinichiro 
Published: August 2012

Abstract
Background: Epidermal growth factor receptor (EGFR) is a transmembrane protein consisting of an extracellular ligand-binding domain, and its activation leads to a multitude of effects including cell proliferation, cell differentiation, angiogenesis, metastasis, and antiapoptosis. EGFR can be a partner of heterodimer of other EGFR family such as HER2 and HER3. EGFR is often overexpressed in non-small cell lung cancer (NSCLC). Anti-EGFR agents including EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have considered to be effective for NSCLC when drug sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR targeting therapies. In this study, we knock-downed EGFR using small interfering RNAs (siRNAs) in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. Materials and methods: We treated 14 NSCLC cell lines including nine EGFR mutant and five EGFR wild-type cell lines by geftinib or siRNAs for EGFR knock-down (siR-EGFR). Three cell line, PC-9-GR-N1, RPC-9, and HCC827-Met, were experimentally established as acquired resistant cells to gefitinib. The anti-tumor effect was determined by MTS or colony formation assay. The protein expression was evaluated using Western blotting. Results: All cell lines showed the expression of EGFR protein and siR-EGFR treatment down-regulated EGFR protein in all 14 cell lines. siR-EGFR suppressed cell viability in 7 of 9 EGFR mutant cells ranged from 8.0% to 73%. PC-9-GR-N1 and RPC-9 also showed inhibition. NCI-H1670 and HCC827-Met harboured EGFR mutation but were not inhibited. Of note, PTEN was deleted in NCI-H1670 and c-MET was amplified in HCC827-Met. Cell viability of all EGFR wild-type cells was not inhibited except NCI-H411. Conclusion: Our results indicated that EGFR can be the therapeutic target of NSCLC with EGFR activation. By contrast, targeting EGFR is not appropriate strategy for tumor of which EGFR is not activated even though EGFR is expressed.
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 7. doi:1538-7445.AM2012-7
Abstract 745: Development of gamma-H2AX assay to assess toxicity and efficacy from chemotherapy in circulating tumor cells (CTCs) and peripheral blood lymphocytes
Authors: Sheikh Hassan S. , Matthew Elizabeth , El-Deiry Wafik S. 
Published: August 2012

Abstract
CTC methodology has been recently adopted following FDA approval of the Veridex CellSearch for the detection of CTCs and offers prognostic value in various solid tumors including breast, colorectal, and prostate cancer. gamma-H2AX is an established marker for double strand breaks from DNA damage, and this is particularly evident and has been seen after exposure to ionizing radiation and exposure to topoisomerase inhibitors. Moreover prolonged gamma-H2AX expression has been observed in repair deficiencies after DNA damage where there may be delays in DNA repair and persistence of H2AX. H2AX may therefore serve as an excellent marker not only of toxicity but the efficacy of the chemotherapy. We have been using human tumor cell lines to expose them to chemotherapeutic agents in the laboratory to detect gamma-H2AX levels and the dynamic changes thereof following exposure to cytotoxic chemotherapy. Our results reveal clear time-dependent upregulation of gamma-H2AX in treated cells. This is being adopted for use on CTCs as well as blood lymphocytes with a goal of making correlations with toxicity to chemotherapy in treated patients as well as use of this assay to mark the efficacy of chemotherapy in CTCs. We are applying quantum dot technology to detection of gamma-H2AX in cells recovered from blood and this is being incorporated into a clinical protocol. This assay has potential to impact on monitoring of chemotherapy with regard to both toxicity and efficacy in the 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 745. doi:1538-7445.AM2012-745
Abstract 762: Therapeutic drug monitoring of Anthracyclines and Taxanes in chemotherapy of breast cancer patients
Authors: Valenzuela Belén , Escudero Vanesa , Rebollo Joseba , Sureda Manuel , Brugarolas Antonio 
Published: August 2012

Abstract
Background: Anthracyclines (A) and Taxanes (T) remain amongst the most active drugs in breast cancer chemotherapy. However, significant toxicities are associated when administered at full doses in a number of patients (pts), so careful dose adjustments should be made in order to optimize their clinical effectiveness. A and T have high inter- and intra-patient variability, and a correlation between exposure and efficacy and toxicity has been demonstrated. Therefore, therapeutic drug monitoring (TDM) of these drugs, based on the individual pharmacokinetic (PK) parameters could personalize doses in order to diminish its toxicity and/or to improve the clinical benefit. Methods: A total of 24 pts (92 cycles) were treated with either single drugs, or combinations of two of these agents, usually with four initial cycles of A and 4 subsequent cycles of T. The initial dose was calculated using body-surface algorithm. Pts were monitored since the first cycle and subsequent doses pharmacokinetically adjusted until the target plasma concentration was reached. Bayesian estimates of individual PK parameters were calculated using a population PK models previously published and used for PK-based dose adjustment. Results: The main results are shown in the following table: 43% of pts treated with A had the initial dose increased by an average of 22% without toxicities grade II, except one pt which developed mucositis grade II. For paclitaxel, initial dose was increased in 25% of patients by an average of 22% with only one case of grade 2 asthenia. However, docetaxel initial dose of 60-75 mg/m2 was more toxic than the other drugs evaluated. The doses were reduced by an average of 22% due to toxicities such as grade 3 neutropenia, grade 2 asthenia or grade 2 leucopenia. Conclusion: Standard dosing regimen of A and T in breast cancer pts could be optimized by TDM in order to achieve the target plasma concentration during the chemotherapy treatment and ensure that pts receive the right dose.

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 762. doi:1538-7445.AM2012-762
Abstract 852: ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice
Authors: Dinkel Victoria , Anderson Deborah , Winski Shannon , Winkler James , Koch Kevin , Lee Patrice A. 
Published: August 2012

Abstract
ARRY-380 is an orally active, potent small molecule targeting ErbB2 inhibitor currently in clinical development in patients with ErbB2+ metastatic breast cancer (MBC). This compound has shown excellent activity in numerous SC mouse tumor models including breast (BT-474, MDA-MB-453), ovarian (SK-OV-3) and gastric (N87) carcinoma models. In breast cancer patients, brain metastases are a serious unmet medical need. Patients with ErbB2+ breast cancer have a significantly increased incidence of brain metastases following trastuzumab therapy. Here we demonstrate significant single agent activity of ARRY-380 in two ErbB2+ intracranial mouse xenograft models. For these studies, female nude mice received intracranial implantations of tumor cells (either NCI-N87 or BT-474) by direct injection into the brain parenchyma (via the sagittal suture). In pilot studies, we demonstrated that the blood brain barrier was not disrupted by mechanical injections and that increasing tumor burden correlates negatively with neurologic outcome, body weight and survival. In the N87 studies, animals received treatments beginning on Day 2 post-implantation and continuing for up to 6 weeks. Dose groups (n=12/group) were vehicle, ARRY-380 at MTD (75 mg/kg, PO, BID) or lapatinib at MTD (50 mg/kg, PO, BID). All animals in the vehicle- or lapatinib-treated groups did not survive beyond Day 22. In the ARRY-380-treated-group, 75% of the animals were alive on Day 43. Brain PK/PD was also evaluated in the N87 model. ARRY-380 and its active metabolite caused a significant reduction in brain pErbB2 (80%). In the BT-474 model, animals received treatments beginning on Day 2 post-implantation and continuing for up to 8 weeks. Dose groups (n=13/group) were vehicle, ARRY-380 at MTD (75 mg/kg, PO, BID), lapatinib at MTD (50 mg/kg, PO, BID) or neratinib at MTD (40 mg/kg, PO, QD). On Day 56, survival in the ARRY-380 group was 69% while survival rates in the vehicle, lapatinib or neratinib-treated groups were 23%, 8% and 23%, respectively. Thus ARRY-380 treatment significantly enhances survival in two ErbB2 driven intracranial tumor xenograft models, with superior activity compared to other ErbB2 agents in these studies. Additionally, ARRY-380 has demonstrated durable clinical activity in heavily pre-treated patients with ErbB2+ MBC. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases.
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 852. doi:1538-7445.AM2012-852
Abstract 871: Dual inhibition of PI3K and Erk1/2 shows synergy and efficacy in human tumor cells, either by using drug combinations or novel dual PI3K/Erk inhibitors
Authors: Seipelt Irene , Gerlach Matthias , Blumenstein Lars , Mueller Gilbert , Guenther Eckhard , Engel Jürgen , Teifel Michael 
Published: August 2012

Abstract
The Ras/Raf/Mek/Erk and the PI3K/Akt signaling pathways are frequently deregulated in cancer due to activation of upstream receptors, decreased expression of tumor suppressors like PTEN or activating mutations of Ras, B-Raf or PI3K. Several clinical studies with kinase inhibitors targeting single members of the Ras/Raf/Mek/Erk or the PI3K/Akt pathway are ongoing. However, preclinical and clinical trials indicated limited success by single pathway inhibition and different resistance mechanisms were defined. Further clinical trials with drug combinations of Ras/Raf/Mek/Erk and PI3K/Akt suppressors have been initiated, suggesting a more favorable outcome than targeting only one single pathway, Ras/Raf/Mek/Erk or PI3K/Akt. We performed in-vitro combination experiments with Raf, Mek or Erk inhibitors and PI3K or Akt inhibitors in several human tumor cell lines. Strong synergy was achieved with various combinations including the Mek inhibitor CI-1040 and the PI3K inhibitor GDC-0941 (CI = 0.17) or the Erk inhibitor AEZS-131 and the PI3K inhibitor D-117073 (CI = 0.23) in A549 cells. Also Raf inhibitors like Sorafenib and Zelboraf were combined with different PI3K inhibitors, resulting in synergistic anti-proliferative activity. Due to the attractiveness of parallel inhibition of the Ras/Raf/Mek/Erk and PI3K/Akt pathways, we developed AEZS-136 that concurrently inhibits Erk1/2 (IC50 ∼ 50nM) and PI3K (IC50 ∼ 100nM) by an ATP competitive mode of action. Derivatives of the dual PI3K/Erk inhibitor were co-crystallized with Erk2 and PI3Kα enabling an optimization process by SAR driven medicinal chemistry. The anti-proliferative efficacy of AEZS-136 was evaluated in more than 40 human tumor cell lines and physico-chemical as well as in-vitro ADMET properties were widely assessed. Furthermore, the in-vivo pharmacokinetics and anti-tumor efficacy was explored. AEZS-136 was well tolerated and showed dose dependent inhibition of human colon tumor growth of up to 74% in a Hct116 mouse model. Here we present the concept of dual targeting of the Ras/Raf/Mek/Erk and the PI3K/Akt pathways, either by using drug combinations or our novel dual PI3K/Erk inhibitor. AEZS-136 is a small molecule in preclinical development showing a uniquely advantageous kinase inhibition profile. Broad clinical anti-tumor activity is expected for AEZS-136 in tumors with deregulated Ras/Raf/Mek/Erk and PI3K-Akt signaling.
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 871. doi:1538-7445.AM2012-871
Abstract 93: Defining the roles of COIL and WIPI1 in breast cancer metastasis
Authors: Lee Misan , Cheung Grace , Nair Ranju , Done Susan 
Published: August 2012

Abstract
Metastasis of cancerous cells to distant sites is the major cause of death from breast cancer. In a previous study, we performed aCGH on breast invasive duct carcinoma samples with and without lymph node metastases and identified regions of genomic amplification that are associated with lymph node metastasis. These were subsequently validated by q-PCR. Within the 17q22-24 region, we have identified four genes likely to contribute to metastasis based on published data: COIL, WIPI1, TMEM100, and SLC16A6. We are using RNAi and ectopic over-expression to characterize these genes with in vitro functional assays for proliferation, migration, invasion, and survival. We used qRT-PCR analysis on a panel of seven breast cancer cell lines of varying invasiveness: MDA-MB-157, MDA-MB-231, MDA-MB-468, BT-549, CAMA-1, HS578T, MCF-7, and SKBR-3. We identified that WIPI1 and COIL were expressed in the majority. WIPI1 is up-regulated in a variety of tumor cells; studies suggest WIPI1 can activate autophagy by suppressing TORC1. Autophagy can inhibit cancer by maintaining genome stability via disposing of damaged mitochondria and peroxisomes. In clinical data obtained from 298 breast cancer patients, we observed high expression of WIPI1 to be associated with higher survival and lower breast cancer relapse. Alternatively, autophagy can also provide a survival mechanism for tumors with restricted blood supply and resistance to chemotherapy. This is in agreement with our observation of high WIPI1 protein expression in highly invasive breast cancer cell lines. We are over-expressing WIPI1 in SKBR-3 and knocking it down in BT-549 in vitro. WIPI1 could help determine the role of autophagy in tumor initiation processes such as proliferation and invasion, and in maintenance of tumor cells following therapy. COIL is found in a diffuse nucleoplasmic pool and in Cajal bodies (CBs). The role of diffuse COIL is still unclear, but CBs, involved in the formation of macromolecular complexes and found more in cells with high transcriptional activity, require COIL for proper formation and localization. We observed high expression of COIL protein in cell lines with higher proliferation index, noticeably in ER positive cell lines such as CAMA1 and absence in a non-tumorogenic cell line MCF10A. We are investigating the association of COIL with proliferation, invasion and migration abilities by over-expression and knockdown of the COIL protein in MDA231 and MCF7 breast cancer cells. We found from clinical data obtained from 245 breast cancer patients that high expression of COIL resulted in lower survival and a higher risk of relapse. This suggests that COIL may be a potential therapeutic target.
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 93. doi:1538-7445.AM2012-93
Abstract LB-375: Inactivation of the deubiquitinase USP44 is an early event in the formation of colorectal cancer
Authors: Sloane Mathew , Hesson Luke , Wong Jason , Pimanda John , Bourke Michael , Hawkins Nick , Ward Robyn 
Published: August 2012

Abstract
Colorectal cancer (CRC) develops from intraepithelial neoplasms known as adenomas. Genomic profiling of these premalignant lesions presents an opportunity to discover molecular changes that can lead to colorectal cancer. Some of the earliest changes are thought to be epigenetic, including hypermethylation of the promoters of key tumour suppressor genes. To identify such changes in colon cancer we performed whole genome DNA methylation profiling (MBD-Seq) on three adenomas and matched normal mucosa. We then validated epigenetic changes in a cohort of 105 adenomas using COBRA, bisulphite sequencing and quantitative RT-PCR. In each adenoma, we identified 1598, 556 and 331 promoter CpG islands respectively that were hypermethylated when compared with matched normal mucosa. Two of the three adenomas showed CpG island hypermethylation of the USP44 gene, a deubiquitinase previously shown to affect mitotic progression by deubiquitinating Cdc20, a regulator of the Anaphase Promoting Complex. In the absence of USP44, cells prematurely enter anaphase resulting in accelerated mitotic progression. Using COBRA and bisulphite sequencing we show that hypermethylation of USP44 occurred in 100% of 18 CRC cell lines, 79% of 105 adenomas, but in only 10% of 45 matched normal mucosa. In adenomas, USP44 hypermethylation correlated with a &gt;2-fold decrease in gene expression. Reduced expression has also been reported in glioblastoma, B-ALL, breast, colorectal, esophageal, kidney and testicular cancer. We show that treatment of four CRC cell lines with the DNA demethylating agent 5-Aza-2′-deoxycytidine (5azaDC) resulted in a 10-250 fold increase in USP44 expression. In summary, we show that epigenetic inactivation of the deubiquitinase USP44 is a frequent and early event in the formation of colon cancer. Taken together with reports that USP44 expression is reduced in a range of solid organ and haematological malignancies, we propose that epigenetic inactivation of this gene may represent an important yet hitherto unrecognized event in tumour formation.
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 LB-375. doi:1538-7445.AM2012-LB-375
Abstract LB-385: The role of tumor suppressing microRNA let-7 in undifferentiated nasopharyngeal carcinoma
Authors: Wong TS , Gao W , Li JZH , Chan JYW 
Published: August 2012

Abstract
AIMS:This study aimed at evaluating the potential anti-proliferative effects of the microRNA let-7 family in nasopharyngeal carcinoma (NPC) cells. In addition, the association between let-7 suppression and DNA hypermethylation is examined. MATERIALS AND METHODS:Levels of mature let-7 family members (-a, -b, -d, -e, -g, and -i) in normal nasopharyngeal cells (NP69 and NP460) and nasopharyngeal carcinoma cells (HK1 and HONE1) were measured by real-time quantitative PCR. Cell-proliferation assay and c-Myc immunohistochemical staining were performed on NPC cells transfected with let-7 precursor molecules. In addition, expression changes in let-7 family members in response to demethylating agents (5-azacytidine and zebularine) were also examined. RESULTS:In comparison with the normal nasopharyngeal cells, let-7 (-a, -b, -d, -e, -g, and -i) levels were reduced in nasopharyngeal carcinoma cells. Ectopic expression of the let-7 family in nasopharyngeal carcinoma cells resulted in inhibition of cell proliferation through downregulation of c-Myc expression. Demethylation treatment of nasopharyngeal carcinoma cells caused activation of let-7 expression in poorly differentiated nasopharyngeal carcinoma cells only. CONCLUSION:Our results suggested that miRNA let-7 might play a role in the proliferation of NPC. DNA methylation is a potential regulatory pathway, which is affected when let-7 is suppressed in NPC cells. However, the extent of DNA hypermethylation/hypomethylation in regulating let-7 expression requires further elucidation.
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 LB-385. doi:1538-7445.AM2012-LB-385