bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 621: High-dose gefitinib overcomes the resistance to gefitinib related to hepatocyte growth factor
Authors: Kashihara Hiromi , Ichihara Eiki , Takata Saburo , Ohashi Kadoaki , Kubo Toshio , Takeda Hiromasa , Fujii Masanori , Takigawa Nagio , Tanimoto Mitsune , Matsumoto Kunio , Kiura Katsuyuki 
Published: February 2011

Abstract
Molecular targeted agents are being a mainstay in non-small cell lung cancer. Dramatic responses to the epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitor (TKI) are observed in advanced non-small cell lung cancer (NSCLC), especially with EGFR mutation. Different from cytotoxic agents, it remains unclear whether EGFR-TKI exerts its anti-tumor effect dose-dependently. Gefitinib could not show survival benefit in previously treated unselected patients with NSCLC in a randomized phase III trial, whereas erlotinib did. The difference is considered resulting from the fact that erlotinib was dosed at its maximum-tolerated dose (MTD), while gefitinib was dosed at about one third of its MTD. To investigate the dose-dependency of gefitinib in the cells harboring mutated EGFR, we compared two doses of gefitinib (15 or 50 mg/kg) using PC-9 (adenocarcinoma of lung) xenografts. Both doses of gefitinib reduced tumors. However, the tumors regrew in the low-dose group after several weeks of treatment, whereas did not in the high dose group. This result indicates that gefitinib might have the dose-dependency in the tumors harboring mutated EGFR. We resected tumors at 10 weeks after gefitinib treatment. The removed tumors did not acquired T790M mutation and MET amplification. Interestingly, the cells (PC-9/RX) that were derived from the xenograft tumors treated with low-dose gefitinib remained the sensitivity to gefitinib. Thus, we investigated hepatocyte growth factor (HGF) as the environmental factor. Tumor tissues treated with gefitinib were positively stained with anti-mouse HGF. Mouse HGF mRNA and protein expression in the tumor tissues treated with gefitinib were significantly high when compared to those treated with vehicle alone, and similar results were obtained by ELISA. We confirmed that mouse HGF induced resistance to gefitinib in an ex vivo experiment. To elucidate the role of HGF in vivo, PC-9 xenografts were treated with gefitinib in combination with rabbit anti-HGF antibody. The combination of gefitinib with anti-HGF antibody inhibited tumor growth partially compared with the low-dose gefitinib alone. Taken together, HGF might induce resistance to low-dose of gefitinib treatment in an in vivo xenograft model before the tumor cells themselves acquired the resistant genetic changes.
In conclusion, higher-dose of gefitinib might prevent resistance to gefitinib related to HGF and produce longer response duration.
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 621.
Abstract 625: Transcription factor slug conferring resistance To EGFR tyrosine kinase inhibitor gefitinib
Authors: Chang Tzu-Hua , Shih Jin-Yuan , Tsai Meng-Feng , Yang Chih-Hsin , Yang Pan-Chyr 
Published: February 2011

Abstract
Purpose: Somatic EGFR mutations of non-small cell lung cancer (NSCLC) are reported to be associated with clinical responsiveness to tyrosine kinase inhibitor gefitinib. Despite the dramatic responses to gefitinib, most patients ultimately have a relapse. The underlying mechanism of the drug resistance is not well clear. Recently, many studies have shown that epithelial to mesenchymal transition (EMT) is involved in resistance to gefitinib in EGFR. Zinc finger transcription factor slug is one of the EMT regulators. In this study, we will investigate whether the slug plays a role in the gefitinib resistance. Materials and Methods: PC9/IR (gefitinib-resistant cell line) was isolated from PC9 (gefitinib-sensitive cell line) after long-term treatment of gefitinib. To identify the factors involved in gefitinib resistance, we analyzed the expression levels of EMT regulators (Slug, Snail, Twist, Zeb-1) in PC9/IR and PC9 cells using quantitative real time PCR and western blot. To investigate the association of Slug and gefitinib-induced resistance, we also engineered to stably express Slug and short hairpin RNA targeting Slug transcript in PC9 and PC9/IR, respectively. Results: The findings showed that mRNA and protein levels of Slug obviously increased in PC9/IR comparing with PC9 and expression of other EMT regulators Snail, Twist, Zeb-1 were similar between these two cell lines. After gefitinib treatment, PC9/IR expressing shRNA against Slug underwent apoptosis and activation of the intrinsic apoptosis pathway. Ectopic expression of Slug protected PC9 cells from undergoing apoptosis in response to gefitinib treatment. Knockdown the expression of slug reversed gefitinib resistance of PC9/IR cells by restoring Bim expression. Conclusions: These results suggest that expression of slug may contribute to resistance to gefitinib in PC9/IR and may be a useful target for treatment of resistance to EGFR tyrosine kinase inhibitor.
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 625.
Abstract 626: Therapeutic effect of HGF inhibitors against HGF-induced EGFR-TKI resistance in lung cancer harboring EGFR mutations
Authors: Yano Seiji , Wang Wei , Li Qi , Donev Ivan S. , Takeuchi Shinji , Yamada Tadaaki , Matsumoto Kunio , Nishioka Yasuhiko , Sone Saburo 
Published: February 2011

Abstract
Introduction: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, the responders invariably acquire resistance to EGFR-TKIs. Two mechanisms, second-site point mutation that substitutes methionine for threonine at position 790 (T790M) in EGFR and amplification of MET proto-oncogene, which contribute to acquired resistance to EGFR-TKIs have been reported. As the third mechanism, we recently demonstrated that hepatocyte growth factor (HGF), specific ligand for MET, induced resistance to EGFR-TKIs. The purpose of this study was to examine whether inhibitor of HGF could overcome resistance to EGFR-TKIs induced by HGF in NSCLC cells with EGFRmu.
Results: HGF induced the resistance to gefitinib and erlotinib in lung cancer cells (PC-9 and HCC827) with EGFRmu, by restoring Akt phosphorylation through MET but not EGFR or ErbB3. These NSCLC cells also became resistant to EGFR-TKIs when co-cultured in vitro with HGF-producing fibroblasts and co-injected into SCID mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4 successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo.
Conclusions: These findings indicate that HGF inhibitor, such as anti-HGF antibody and NK4, may be useful for controlling HGF-induced EGFR-TKI resistance in NSCLC harboring EGFRmu in humans.
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 626.
Abstract 630: Interleukin-8 as a potential mediator for renal cell carcinoma resistance to antiangiogenic sunitinib therapy
Authors: Huang Dan , Ding Yan , Zhou Ming , Rini Brian , Petillo David , Qian Chao-Nan , Kahnoski Richard , Futreal P. Andrew , Furge Kyle A. , Teh Bin Tean 
Published: February 2011

Abstract
Sunitinib is considered the first line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients exhibit progressive disease after about one year of treatment. The mechanisms of progression are poorly understood. The aim of this study was to evaluate the mechanism of resistance to sunitinib and to identify potential targets to overcome sunitinib resistance. We generated xenograft models that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, which indicated that an escape from anti-angiogenesis occurred in these tumors. This escape coincided with increased tumor secretion of interleukin-8 (IL-8) into the plasma. Co-administration of an IL-8 neutralizing antibody resensitized these tumors to sunitinib treatment, demonstrating the functional contribution of IL-8 to sunitinib resistance. Immunohistochemical staining showed that IL-8 expression was elevated in ccRCC tumors from patients who were refractory to sunitinib treatment, indicating IL-8 levels may predict clinical response to sunitinib. In conclusion, our results demonstrate that IL-8 is an important contributor, among others, to sunitinib resistance in ccRCC. IL-8 may serve as a therapeutic target for treatment of sunitinib resistant ccRCC, as well as a biomarker for both acquired and intrinsic sunitinib resistance.
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 630.
Abstract 631: Androgen receptor(AR) splice variants inhibit responses to IGF-IR inhibition in prostate cancer
Authors: Sun Shihua , Haugk Kathleen , Vessella Robert L. , Nguyen Holly , Soriano Kathryn , Plymate Stephen R. 
Published: February 2011

Abstract
Constitutively active splice variants of the androgen receptor (AR) are frequently expressed (59% of metastases) following castration in prostate cancer patients and are associated with earlier tumor recurrence compared to tumors containing only wild-type (wt) AR. In most tumors the variant is expressed along with wt-AR. When wtAR and variant AR are expressed in cells following castration there is a marked decrease in IGF type 1 receptor expression (IGF-IR), an AR target whose expression is increased by wtAR. In order to understand these findings we expressed the AR splice variant in which exons 5, 6, and 7 are skipped during AR splicing resulting in constitutively active ARv567es along with wtAR in a prostate cancer cell line not expressing AR, M12, as well as ARv567es in AR positive LnCaP cells. In both lines ARv567es was found only in the nucleus in the absence of ligand but wtAR had also been transported to the nucleus and absolute levels of AR protein were increased in the absence of ligand in cells expressing the variant. The increase in wtAR protein is due to decreased degradation of wtAR associated with ARv567es. When ligand was added, PSA response was increased 5-fold over cells transfected only with wtAR. Further, whereas transfection with wtAR enhances IGF-IR expression and response to IGF-I ligand, in the presence of ARv567es IGF-IR expression in response to IGF-I was suppressed. When ARv567es was HA tagged and expressed along with wtAR pull-down of ARv567es with HA resulted in concomitant precipitation of wtAR. Subsequent deletion analysis of ARv567es demonstrated direct binding between the two ARs in specific cystine-rich domains. Further, wtAR-induced IGF-IR expression is a non-genomic AR cytoplasmic action through binding to src and MAPK phosphorylation. Although ARv567es binds src, phosphorylation of MAPK does not occur. Finally, when LnCaP cells expressing ARv567es were grown sc with MatrigelTM in immuno-compromised mice there was no response to castration as opposed to slowed growth of LnCaP controls. These data indicate that the presence of the castration-induced ARv567es not only effects progression of prostate cancer by its own constitutive activity but also changes the function of the wt or full-length AR and provides an additional mechanism for AR-induced prostate cancer progression following castration.
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 631.
Abstract 637: Filling the gap between preclinical and clinical oncology drug evaluation- Molecular profiling and PD biomarkers on HuPrimeTM tumors models
Authors: Chen Taiping , Song Xiaoming , Chen Dawei , Yu Shijun , Wery Jean-Pierre , Chen Yiyou 
Published: February 2011

Abstract
Most anticancer drug candidates, currently in clinical trials, have clear targets in molecular and cellular systems. However, such molecular targets are not always affected (or not correlated with efficacious endpoints) when the candidate is evaluated in a clinical setting. The gap between preclinical and clinical drug evaluation remains the bottle neck for anticancer drug development. There is an urgent need to develop better biological tools and models to ease the transition between in vitro and in vivo, and between preclinical and clinical settings. In our translational platforms, 170 human primary tumor models (HuPrimeTM) have been established directly from tumor fragments of the patients with many cancer types. In order to pick the best models for evaluation of targeted therapeutics, we have conducted a comprehensive molecular profiling of our models. This profiling includes Affymetrix whole genome expression, Illumina 1400 SNP of cancer related cancer genes for amplification, deletion, and allelic imbalance. Methylation statuses for selected gene sets were also analyzed by SuperArray platform. Genomic amplifications were further confirmed with protein analysis by western blot or immunohistochemistry. The models selected in this way have facilitated pharmacodynamic (PD) biomarker strategies. We have developed a unique platform combining our novel HuPrimeTM xenograft models with molecular profiling and PD biomarker exploration. We have now validated immunohistochemistry (IHC) assays on many molecules covering most signaling pathways that are involved in proliferation, apoptotic, necrotic, and cell cycle regulation, G2M phase arrest, DNA damage response, etc. Additional markers including angiogenesis have also been validated for certain therapeutic compounds. To illustrate the usefulness of our platform, we have applied it to understand the pharmacodynamic changes (at the molecular level) which are associated with the activity of Sunitinib, Sorafenib and Tarceva in several HuPrimeTM models. The PD biomarkers validated in this approach have potential for clinical application and patient stratification.
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 637.
Abstract 639: Measuring PI3K and MAPK pathways inhibition, comparison between conventional IHC and AQUA-TMA technology
Authors: Prudkin Ludmila , Serra Violeta , Aura Claudia , Jimenez José , Scaltriti Maurizio , Baselga José 
Published: February 2011

Abstract
The incorporation of molecular biomarkers to assess therapy efficacy is crucial in both preclinical and clinical phases of drug development. New generation targeted therapy requires sensitive and robust analyses that accurately measure up- or down-regulation of specific pathways in response to a given therapeutic strategy. Paraffin embedded tissue is the sample commonly available in the clinic, and immunohistochemistry (IHC) has become the gold standard for biomarker detection. Although the reproducibility of this method has improved over time, IHC remains a semi-quantitative and subjective evaluation (H-score) of both intensity and expression extent of a given protein. These drawbacks can be by-passed by using automated quantitative analysis-tissue microarray (AQUA-TMA) technology. This platform analyzes double immunofluorescence (dIF) images and provides precise and objective staining quantifications using the AQUAnalysis software.
In this work we show a comparison between conventional IHC and AQUA-TMA technology in assessing the efficacy of Hsp90 inhibition, PI3K/mTOR inhibition and Akt inhibition in a HER2-driven breast cancer xenograft model measuring a number of biomarkers.
Both IHC and dIF techniques have been performed on TMAs and several molecular markers have been evaluated. Specifically, we have measured the levels of HER2, AKT and MAPK total proteins as well as phosphorylation of AKT, MAPK, PRAS40, p70-S6K and S6RP in response to the aforementioned therapies. Moreover, since the AQUAnalysis software also recognizes cellular and sub-cellular compartments of fluorescent signals, we investigated FOXO nuclear translocation.
Our results show that the AQUA technology adds more accuracy than IHC to the assessment of the studied biomarkers. TMAs are readily scanned and analyzed by the software, and the quantification values provided by the system are directly used for statistical analysis.
Our work suggests that, although IHC and H-Score is the current method of evaluation, an accurate and unbiased measurement of molecular markers using the AQUA-TMA platform can improve the assessment of target inhibition in both preclinical and clinical settings.
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 639.
Abstract 642: Vimentin is a novel anticancer therapeutic target
Authors: Zhu Quansheng , Lahat Guy , Bolshakov Svetlana , Liu Jeffery , Torres Keila , Langley Robert R. , Lazar Alexander J. , Hung Mien Chie , Lev Dina 
Published: February 2011

Abstract
Vimentin is a ubiquitous mesenchymal intermediate filament supporting mechano-structural integrity of quiescent cells while participating in adhesion, migration, survival, and cell signaling processes via dynamic assembly/disassembly in activated cells. Soft tissue sarcomas and some epithelial cancers exhibiting “epithelial to mesenchymal transition” phenotypes express vimentin. Withaferin-A (WFA), a naturally derived bioactive compound, may molecularly target vimentin, so we sought to evaluate its effects on tumor growth in vitro and in vivo thereby elucidating the role of vimentin in drug-induced responses. WFA elicited marked apoptosis and vimentin cleavage in vimentin-expressing tumor cells but significantly less in normal mesenchymal cells. This proapoptotic response was abrogated after vimentin knockdown or by blockade of caspase-induced vimentin degradation via caspase inhibitors or overexpression of mutated caspase-resistant vimentin. Pronounced anti-angiogenic effects of WFA were demonstrated, with only minimal effects seen in non-proliferating endothelial cells. Moreover, WFA significantly blocked soft tissue sarcoma growth, local recurrence, and metastasis in a panel of soft tissue sarcoma xenograft experiments. Apoptosis, decreased angiogenesis, and vimentin degradation were all seen in WFA treated specimens. In light of these findings, evaluation of WFA, its analogs, or other anti-vimentin therapeutic approaches in soft tissue sarcoma and ”epithelial to mesenchymal transition” clinical contexts is warranted.
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 642.
Abstract 644: A novel Gemini vitamin D analogue represses the expression of a stem cell marker CD44 in breast cancer
Authors: So Jae Young , Lee Hong Jin , Smolarek Amanda K. , Paul Shiby , Maehr Hubert , Uskokovic Milan , Cai Li , Liu Fang , Suh Nanjoo 
Published: February 2011

Abstract
Breast cancer stem cells are defined as cancer cells with self-renewal capacity. Cancer stem cells are resistant to current chemotherapy and radiation, making it difficult to investigate the mechanisms of resistance and the therapeutic targets of the tumor initiating cell population. Recently, CD44 has been recognized as a useful cell-surface marker for detecting breast cancer stem cells, and the CD44+/CD24- phenotype selects a population with stem cell properties similar to basal-like cancer cells. CD44 is a multi-functional transmembrane protein involved in cell proliferation, angiogenesis, invasion and metastasis. The CD44 positive subpopulation of breast cancer cells are enriched in residual breast cancer cell populations after conventional therapies, suggesting that CD44 positive cells may be responsible for the recurrence of cancer and therefore it may be an important therapeutic target. We have previously shown that novel Gemini vitamin D analogs inhibit the proliferation of breast cancer epithelial cells and suppress tumorigenesis in different animal models of breast cancer. Since therapies targeting CD44 by vitamin D have not been investigated, we examined whether a novel Gemini vitamin D analog regulates CD44 expression in cultured human breast cancer cells or in mammary tumors. In basal-like MCF10DCIS.com human breast cancer cells, the Gemini vitamin D analog BXL0124 significantly inhibited the expression of CD44 protein and reduced the transcriptional activity of the CD44 promoter in vitro. To evaluate the inhibitory effects of Gemini vitamin D on CD44 expression in vivo, MCF10DCIS.com cells were xenografted into immunodeficient mice. When administered intraperitoneally (0.1 microgram/kg body weight) or orally (0.3 microgram/kg body weight) once a day for 6 weeks, Gemini vitamin D BXL0124 inhibited tumor growth and markedly decreased the expression of CD44 in the xenograft tumors. To determine whether the repression of CD44 is dependent on the vitamin D receptor (VDR), siRNA VDR was employed. The repression of CD44 expression by BXL0124 was significantly blocked by siRNA VDR in MCF10DCIS.com cells, indicating that the regulation of CD44 expression by BXL0124 is a VDR-dependent event. Taken together, the novel Gemini vitamin D analog inhibits CD44 expression in MCF10DCIS.com cells in vitro and in xenograft tumors, suggesting an inhibitory role of Gemini vitamin D analogs on cancer stem cells.
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 644.