bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B34: Receptor tyrosine kinases (RTKs) profiling and its role in advanced gastric cancer.
Authors: Hong Soojung , Ahn Jung Ryun , Zhang Xianglan , Lee Ha-young , Kim Hye Ryun , Lee Choong-kun , Lim Seungtaek , Han Jung Woo , Rha Sun Young 
Published: June 2012

Abstract
Background: Receptor tyrosine kinase (RTK) activation is the starting point of intracellular signaling cascades that control cellular process such as proliferation, differentiation, migration and survival and aberrant RTK activation may promote cancer initiation and progression. The purpose of this study was to determine the frequency and the influence of major RTKs including EGFR, HER-2, c-MET, and FGFR-2 expression on the outcomes of gastric cancer patients.
Methods: Between January 2000 and December 2004, 122 patients with advanced gastric cancer in our institute were selected. All patients underwent gastrectomy and D2 lymph node dissection with a curative aim and pathologically confirmed N3 stage without distant metastasis. Formalin-fixed paraffin-embedded (FFPE) tissue specimens were examined for the expression of EGFR, HER-2, c-MET, FGFR-2 by immunohistochemistry (IHC). The score for expression was assessed by the independent pathologist with weighted histoscore method. We defined positive result as the expression of 3+ in IHC for each RTK.
Results: Among 4 RTKs, c-MET expression showed highest frequency as 31 patients (25.4%) followed by FGFR-2 (13; 11.2%), HER-2 (10; 8.5%) and EGFR (6; 5.0%). The majority of samples (58.2%) were negative (wild type) for all four markers. Fourteen patients (11.5%) showed co-expression for these RTKs; one patient was quadruple positive, and the others showed double positivity for c-MET and one of 3 other markers. There were no significant correlations between each biomarker and clinic-pathologic parameters such as patient's gender, differentiation, T stage, lymphovascular invasion, Lauren classification or the number of LN metastasis. With the follow-up period of 21.5 months (0.5–115.7), median overall survival of all patients was 20.9 months (95% CI, 15.2–26.6) and median disease-free survival (DFS) was 17.1 months (95% CI, 9.4–24.8). Based on the status of each receptor, survival outcome was only associated with c-MET over-expression; median DFS of 10.8 months in c-MET positive patients and 22.0 months in c-MET negative patients (p=0.04). Median DFS in patients with co-expression of RTKs showed poorer trend than single marker positive group and wild type group (10.8m, 15.7m, and 19.4m, respectively; p=0.27).
Conclusion: We evaluated the expression pattern with four major RTKs in relatively homogenous subgroup of gastric cancer patients with pathologic N3. c-MET over-expression could be a prognostic biomarker for DFS in these patients, suggesting the significant role of c-met in gastric cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B34.
Abstract B65: Curcumin, a novel inhibitor of ATR-CHK1 pathway, suppresses homologous recombination and DNA damage checkpoint and enhances the sensitivity to PARP inhibitors.
Authors: Ogiwara Hideaki , Yokota Jun , Kohno Takashi 
Published: June 2012

Abstract
Curcumin is a major chemical component of turmeric (curcuma longa) and is used as a spice to give a specific flavor and yellow color in Asian foods. Here we show that treatment of (HeLa) cells with curcumin suppresses DNA damage checkpoint response and homologous recombination repair (HRR). Curcumin inhibited the phospohrylation of CHK1, but not of ATM and CHK2, induced by DNA damage. Furthermore, cells treated with curcumin failed to form ionizing radiation (IR), hydroxyurea (HU) or camptothecin (CPT)-induced RAD51 foci, but not RPA32, 53BP1 and BRCA1 foci. These results suggested that curcumin suppressed HRR and DNA damage checkpoint response through inhibition of the ATR-CHK1 pathway. In fact, curcumin led to accumulate DSBs and increase the apoptotic and necrotic cell death induced by a poly(ADP-ribose polymerase (PARP) inhibitor. It was noted that curcumin enhanced the sensitivity of cancer cells to the PARP inhibitor, which is a promising anti-cancer drug that selectively kills cells deficient for DNA damage response (DDR) including HRR and DNA damage checkpoint response. Taken together, combination of the PARP inhibitor with curcumin was indicated to have a potential to enhance the efficacy of PARP inhibitor-based cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B65.
Abstract B90: Nonviral delivery of apoptin for the treatment of brain tumor in a newly established brain tumor xenograft.
Authors: An Songhie , Choi Sunghyun , Nam Kihoon , Park Jong-Sang 
Published: June 2012

Abstract
We established a brain tumor xenograft to examine the application of gene therapy utilizing a tumor selectively killing gene together with a nonviral gene delivery carrier to treat brain tumor. To do so, we recombined the therapeutic gene apoptin with the JDK vector and delivered it into human brain tumor cells (U87MG) using PAM-RG4 as the gene delivery carrier. Studies in vitro showed that the PAM-R G4/Apoptin polyplex exhibited particularly high transfection activity of over 40% based on fluorescence-activated cell sorting (FACS) analysis and lower cytotoxicity than other control agents. Also, TUNEL assay and DAPI staining verified that tumor cells had undergone apoptosis, which was induced by the apoptin gene. Caspase-3 activity was about two times higher in the therapeutic group. For in vivo studies, the PAM-R G4/Apoptin polyplex was injected into the tumor, which was induced by injecting U87MG cells into the left flank of nude mice and letting them grow to a certain size. The size of the tumor exponentially grew with time in the control groups whereas the treated group did not exhibit any tumor growth. H&E staining and EGFR immunohistochemistry confirmed the existence of the tumor in the control groups and showed that there was no tumor in the treated group. Furthermore, no specific edema, irritation or other kind of harm to the skin could be observed when the polyplex was injected. After reverse-transcript PCR analysis, to verify the expression of apoptin in vivo, TUNEL assay and DAPI staining were, again, utilized to confirm the event of apoptosis in the therapeutic group. These findings indicate that the PAM-RG4/Apoptin polyplex is a very strong candidate for brain tumor therapeutics, due to the synergistic effect of the carrier's high transfection efficiency in neuron cells and the gene's selective apoptosis-inducing activity in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B90.
Abstract B98: AUY922, a novel HSP90 inhibitor: Final results of a phase I dose escalation study in Japanese patients with advanced solid malignancies.
Authors: Onozawa Yusuke , Doi Toshihiko , Yamazaki Kentaro , Watanabe Junichiro , Fuse Nozomu , Yoshino Takayuki , Akimov Mikhail , Robson Matthew , Boku Narikazu , Ohtsu Atsushi 
Published: June 2012

Abstract
Background: AUY922 is a novel, highly potent, non-geldanamycin HSP90 inhibitor, which causes the degradation of multiple oncogenic cellular proteins, and has been suggested to have potential clinical activity in an earlier global Phase I study and ongoing global Phase II studies.
Methods: Single agent AUY922 was administered as a 1 hour weekly IV infusion to Japanese patients (pts) with advanced solid malignancies, This Phase I study was an open-label dose escalation study. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Endpoints included safety, tolerability, preliminary activity, pharmacokinetics and pharmacodynamics.
Results: 31 pts received AUY922 at doses of 8, 16, 22, 28, 40, 54 and 70 mg/m2. Pt characteristics include: median age 60 yrs, 48.4% male, 51.6 % female and WHO performance status 0 (67.7 %) or 1 (32.3 %). Median duration of exposure was 7.3 weeks (range; 0.1, 55.0). The most frequently reported adverse events possibly related to AUY922 were diarrhea-20 pts, (64.5%), night blindness-13 pts, (41.9%), nausea-7 pts (22.6%), fatigue-6 pts (19.4%), rash-6 pts, (19.4%), decreased appetite-5 pts, (16.1%) and vomiting-5 pts (16.1%). Visual symptoms (grade 1–2 and mostly reversible) including night blindness and blurred vision were reported at doses of 22 mg/m2 and higher. A single patient at the 54 mg/m2 dose experienced a dose limiting toxicity of grade 3 fatigue and anorexia. Considering the safety data from a preceding global Phase I study and the potential increase of visual toxicity risk, 70 mg/m2 was declared as the recommended Phase II dose (RPTD) consistent with the RPTD found in the global Phase I study. Stable disease (SD) for at least 8 weeks was reported in 10 pts and 1 rectal carcinoid pt reported a confirmed partial response (PR). Blood concentration of AUY922 reached the peak at the end of infusion and declined slowly with a flat terminal phase.
Conclusions: Weekly IV infusion of single agent AUY922 was well tolerated at the RPTD of 70 mg/m2, confirming the tolerability of the RPTD found in a preceding global Phase I study. Clinical activity was observed in 1 patient in this study, further supporting efficacy of AUY922, as observed in ongoing global clinical studies, and pharmacokinetic parameters were comparable to those observed in non-Japanese patients in the aforementioned global Phase I study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B98.
Abstract C101: The effect of folate-related SNPs on therapeutic responses to neoadjuvant chemotherapy in breast cancer molecular subtypes.
Authors: Babyshkina Nataliya 
Published: June 2012

Abstract
Background: Breast cancer is a heterogeneous disease, comprising several molecular subtypes with diverse biological behavior, clinical presentations and responses to therapy. Given the important role that folate plays in the availability of methyl groups and in the synthesis and repair of DNA, we examined the relationship between single nucleotide polymorphisms in folate-related genes MTHFR (677C&gt;T, 1298A&gt;C), MTR (2756A&gt;G), MTRR (66G&gt;A), DHFR del19, MTHFD1 (1958G&gt;A), TS (28-bp repeat, 1494del6), RFC1 (80G&gt;A), DNMT3b (149C&gt;T) with therapeutic response to neoadjuvant chemotherapy of breast cancer patients according to molecular subtypes.
Material and methods: This study included 300 patients with histologically diagnosed primary breast cancer who were treated between 1998 and 2008 at the Tomsk Cancer Research Institute. Subgroups were classified on the basis of ER, PR, and HER2 immunohistochemical evaluation. PCR-RFLP analysis was used to determine the MTHFR 677C&gt;T, MTHFR 1298A&gt;C, MTR 2756A&gt;G, MTRR 66G&gt;A, MTHFD1 1958G&gt;A and DNMT3b 149C&gt;T polymorphisms. Genotyping for the DHFR del19, TS 28-bp repeat and TS 1494del6 were based on polymerase chain reaction.
Results: A trend was detected towards accumulation of the MTHFD1(AA) and RFC1(GG) genotypes in triple negative (TN) cases compared with the luminal A group (P = 0.06 and P = 0.07 respectively). In addition, we observed that the DHFR(del19/del19) and MTRR(GA) genotypes tended to show an association with HER2+ subtype (P = 0.06 and P = 0.09 respectively). We found that the TN women carrying MTRR(GG) genotype had a worse clinical response to neoadjuvant chemotherapy compared to luminal A cases but this difference did not reach statistical significance (P = 0.06). Luminal A subtype group with MTHFD1(AA) genotype showed an association with better response to neoadjuvant chemotherapy in comparison TN patients (P=0.03).
Conclusion: Our study indicates that the analysis of folate-related gene polymorphisms may help to identify patient subgroups at high risk for the progression of breast cancer. MTHFD1 (1958G&gt;A) may be considered as a molecular marker associated with more aggressive tumor behavior such as TN cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C101.
Abstract C12: Identification of predictive and pharmacodynamic biomarkers for an FGFR inhibitor.
Authors: Sharp Michael , Sadis Seth , Rhodes Dan , Thompson Neal , Otte Marcus , Alvarez John , King Peter , Winkler Hans , Platero Suso 
Published: June 2012

Abstract
Fibroblast growth factor receptors (FGFRs) are widely expressed in multiple organ systems and are involved in growth and angiogenesis. Mutations, translocations and amplifications in FGFR genes have been observed in several types of cancer. The purpose of this study was to identify biomarkers that may predict sensitivity and may change upon FGFR inhibition.
240 tumor cell lines from different types of cancer were treated with a small molecule FGFR inhibitor and IC50 values were calculated. Mutations, amplifications, deletions, gene expression analysis, and network analysis were used to find biomarkers that were sensitive or resistant to the inhibitor. Xenografts were used to identify pharmacodynamics biomarkers. Tumors from cancer patients were analyzed for FGFR gene amplifications using Fluorescent in situ hybridization.
FGFR1 mRNA overexpression and FGFR2 amplification were identified as sensitive biomarkers while Kras mutation was associated with resistance. Multiple sensitive cell lines (n = 2–4) were found in cells derived from breast, lung, gastric, kidney, lymphoma, sarcoma, melanoma, and endometrial cancer. No sensitive cell lines were found in colorectal, pancreatic, leukemia, myeloma, or ovarian cancer. In human breast cancer cell lines, amplifications were found for FGFR1 (23%), FGFR2 (11%), and FGFR4 (16%). Of the 26 breast cancer cell lines analyzed for FGFR1 amplification, 5 had moderate amplification (4–10 copies) and 1 was highly amplified (&gt;10 copies). In non-small cell lung cancer cell lines, amplifications were found for FGFR1 (37%) and FGFR2 (20%). In xenografts, pS6 and pMAPK levels changed upon compound treatment. FGFR1 and FGFR2 amplifications were also found in prostate (15% and 15%, respectively) tumors from patients.
This study identified biomarkers for an FGFR small molecule inhibitor. These results may provide a rationale for patient selection and patient dosing when using a FGFR inhibitor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C12.
Abstract C130: Inhibition of NF-κB activity promotes radiosensitivity of breast cancer cells in three-dimensional culture via a β1-integrin-mediated pathway.
Authors: Ahmed Kazi M. , Zhang Hui , Park Catherine C. 
Published: June 2012

Abstract
Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves prosurvival signal transduction pathways that prevent radiation-induced cell death. Nuclear factor-κB (NF-κB), a stress-sensitive heterodimeric transcription factor in the regulation of the stress-responsive genes, has been shown to initiate prosurvival signaling in response to ionizing radiation (IR). The cooperative function of NF-κB with other key stress elements in radioresistance has not been clearly defined. We have previously reported that induction of β1-integrin is associated with the enhanced cell survival of breast cancer cells after exposure to clinically relevant doses of IR. Because a typical NF-κB binding site was identified in human β1-integrin promoter region, β1-integrin-mediated resistance to radiation may be regulated by NF-κB. The aim of the present study was to reveal a connection between NF-κB and β1-integrin pathways in radioprotection of malignant T4-2 mammary epithelial cells in 3D lrECM (three-dimensional laminin-rich extracellular matrix). We show that the elevated NF-κB activity was correlated with enhanced clonogenic survival with an increase in total and phosphorylated (Thr 788/789) β1-integrins. Inhibition of NF-κB activation significantly reduced clonogenic survival with the inhibition of β1-integrin, suggesting that NF-κB-mediated induction of β1-integrin is associated with an increased radiation resistance. Treatment of malignant human breast cell colonies, T4-2 with NF-κB activation inhibitor at Day 4 in 3D lrECM before exposure to IR (4-Gy X-ray) resulted in a reduction of the size of colonies. The surviving colonies were associated with a decrease in proliferation and increase in apoptosis, indicating a decrease of resistance to IR. Using an ELISA-based DNA binding assay, we next determined that the binding of NF-κB to its target sequence on β1-integrin promoter region was significantly increased by IR. These data suggest that IR-induced increase in β1-integrin protein expression is mediated by NF-κB activation and subsequent binding of NF-κB to the β1-integrin promoter. Taken together, our results provide the first evidence that NF-κB-mediated β1-integrin expression is responsible for tumor radioresistance. The NF-κB/β1-integrin pathway could provide new insight into the development of new therapeutic modalities to re-sensitize radioresistant tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C130.
Abstract C14: Tissue expression profile of novel tumor biomarkers identified by monoclonal antibodies.
Authors: Arlen Philip M. , Saric Olga , Arlen Myron , Bristol Andrew 
Published: June 2012

Abstract
Background: Monoclonal antibodies (mAbs) were raised against human colon tumor tissue extracts. Antibodies that specifically recognized tumor tissues, but did not cross-react with normal tissues, were selected for further characterization and development as diagnostic reagents and therapeutic candidates. Three mAbs that react with variant forms of MUC5AC, CEACAM molecules, and A33 were identified. The immunohistochemical staining profiles of these antibodies (NEO-101, NEO-201, and NEO-301) will be discussed.
Methods: The three antibodies (NEO-101, NEO-201, and NEO-301) were each biotin-labeled, and used to stain a variety of tumor and normal human tissue types, typically at 10 ug/mL. Binding of the primary antibody was detected using streptavidin-HRP conjugate. Slides were reviewed and scored by light microscopy.
Results: The NEO-101 antibody recognizes a variant form of MUC5AC expressed by colorectal (79%) and pancreatic (48%) cancer tissues. NEO-101 did not significantly cross-react with normal colon or pancreas tissues. Staining appeared to be cytoplasmic, membrane-associated, and elaborated into the lumenal spaces of positively stained tissues. The NEO-201 antibody recognizes variant forms of both CEACAM-5 and CEACAM-6. NEO-201 reacts with a wider variety of tumor tissue types including colorectal (98%), pancreatic (80%), lung (71%), stomach (100%), esophagus (61%), breast (31%), and ovarian (31%). Cross-reactivity to normal tissues was weak and sporadic. The NEO-301 antibody recognizes a variant form of A33, that is expressed by colorectal (46%), pancreatic (52%), lung (65%), and breast (45%) tumor tissues. NEO-301 also does not cross-react significantly with normal tissues. Antibodies NEO-201 and NEO-301 stained both cytoplasm and membranes of tissues examined.
Conclusions: NEO-101, NEO-201, and NEO-301 antibodies react specifically with tumor tissues without significant cross-reactivity to normal tissues, an attractive characteristic for developing effective therapeutic and diagnostic products for oncology indications. We suggest that the antigens they react with are novel variants of commonly known wild type proteins that can be used as biomarker since they do not cross-react with healthy tissues. Interestingly, although these 3 antibodies were generated from extracts of pooled human colon tumor tissues, the variant antigens they cross-react with are not restricted to expression by colon tumor tissues, supporting the idea that variant protein expression may be a general property of tumor cells compared to normal cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C14.
Abstract C142: The development of a miRNA-based therapeutic candidate for hepatocellular carcinoma.
Authors: Daige Chris , Priddy Leslie , Kelnar Kevin , Zhao Jane , Dysart Sarah , Bader Andreas , Brown David 
Published: June 2012

Abstract
Tumor suppressor miRNAs function by regulating multiple cancer-related genes and pathways. The tumor suppressor miRNAs miR-34, let-7, miR-16, miR-26, and miR-145 have proven to be effective in inhibiting tumor growth in mouse models of cancer. Based upon the availability of systemic delivery technologies that provide significant accumulation of siRNAs in liver tumors, we chose to identify tumor suppressor miRNAs that might be used as therapies for hepatocellular carcinoma (HCC). Cell culture studies with mimics of eight tumor suppressor miRNAs revealed five with the capacity to significantly inhibit the proliferation of multiple HCC cell lines. The five miRNA mimics were complexed with several lipid formulations and injected into NOD/SCID mice with orthotopically grown Hep3B liver cancer xenografts. All five miRNAs significantly inhibited the growth of the liver tumors compared to animals treated with formulated negative control miRNAs. Intriguingly, mimics of three of the tumor suppressor miRNAs eliminated detectable tumors. Preliminary studies indicate that the formulated miRNAs are neither toxic nor immunostimulatory. The formulated miRNAs are currently being evaluated for therapeutic activity in mouse models of other cancers and a development program has been initiated in anticipation of creating candidates for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C142.